Benzamide derivative or salt thereof

ABSTRACT

There is provided a compound having a capsaicin receptor VR1 inhibitory activity and useful as a therapeutic agent for various pains including inflammatory pain and neurogenic pain, migraine, cluster headache, bladder diseases including overactive bladder, and the like. 
     A benzamide derivative or a salt thereof wherein a benzene ring is attached to a D ring (a monocyclic or bicyclic hydrocarbon ring or a monocyclic or bicyclic heteroaromatic ring) through an amide bond, the benzene ring is directly bonded to an E ring (a monocyclic or bicyclic hydrocarbon ring or a monocyclic or bicyclic heteroaromatic ring), and the benzene ring is further bonded to A (an amino moiety, a monocyclic or bicyclic heterocycle) through L (a lower alkylene).

TECHNICAL FIELDS

The present invention relates to novel benzamide derivatives or saltsthereof useful as medicaments, particularly, capsaicin receptor VR1(Vanilloid Receptor 1) activation inhibitor, and the medicaments.

BACKGROUND ART

Capsaicin, which is a main component of chili pepper, is an irritantsubstance and induces pain by activating capsaicin receptor VR1 presentin primary afferent sensory nerves (mainly C fibers). VR1 was cloned[Nature 389: 816-824 (1997)] and was found to be a non-selective cationchannel having a high Ca²⁺ permeability. VR1 is activated by not onlycapsaicin but also thermal stimulation or acid (proton) stimulation.Moreover, it was also revealed that inflammation-related substances suchas ATP and bradykinin act on a metabotropic receptor and regulate VR1activity through activation of phospholipase C (PLC)/activation ofprotein kinase C (PKC). Furthermore, it is known that not only a painreaction by capsaicin disappears but also hyperalgesia at inflammationdecreases in VR1-deficit mice [Nature 405: 183-187 (2000)]. From thesefacts, VR1 is considered to participate in pains at various clinicalconditions.

Capsaicin induces pain by activating VR1 but is known to exhibit ananalgesic action inversely by desensitizing afferent nerves throughcontinuous activation and thereby inhibiting subsequent activation.Actually, a capsaicin cream is used for treating neuropathic pains suchas postherpetic neuralgia or pain in diabetic neuropathy andinflammatory pains such as rheumatic joint pain. Moreover, the reasonwhy the bladder dysfunction observed in patients like spinal cord injuryand the like is alleviated by injection of capsaicin or an analogoussubstance, reginiferatoxin (RTX) into bladder is consider to be based ondesensitization of afferent nerves as in the case of the analgesicaction.

Not only desensitization induced by a VR1 agonist but also a VR1antagonist exhibits an analgesic action. It is known that capsazepineknown as a VR1 antagonist from long ago exhibits efficiency forneuropathic pains and inflammatory pains in animal models [J. Pharmacol.Exp. Ther. 304: 56-62 (2003)]. An endogenous ligand for VR1 is unclear,but a plurality of candidate substances have been reported. Anantagonist is considered to exhibit the analgesic action throughinhibition of VR1 activation by competition with these substances. Thus,the inhibition of VR1 activation not only exhibit an analgesic action,but also is expected to lead to prevention or therapy of symptoms anddiseases relevant to VR1 activation.

Therefore, a compound having an inhibitory activity of VR1 activation isconsidered to be useful for various pains including neuropathic painsand inflammatory pains, headaches such as migraine and cluster headache,pruritus, bladder diseases including overactive bladder and interstitialcystitis.

Recently, investigation on the compounds having an inhibitory activityof VR1 activation has been advanced. For example, a pamphlet ofInternational Publication No. 02/08221 (Patent Document 1) describesthat piperazine derivatives represented by the following generalformula:

wherein G, Q, T, and W are the same or different and each represents N,CH, or CR₅, A is absent or represents O, S, or the like, R₃ and R₄ eachindependently represents hydrogen atom, halogen atom, hydroxy, amino,cyano, or the like, R₅ represents cyano, hydroxy, amino, or the like,and R₉ represents halogen atom, cyano, nitro, or the like (cf. PatentDocument 1 for details of the symbols in the formula),can be used for treatment of chronic and acute pains, psoriasis,incontinence of urine, and the like as a ligand for receptor ofcapsaicin receptor.

Moreover, a pamphlet of International Publication No. 03/014064 (PatentDocument 2) describes that amine derivatives represented by thefollowing general formula:

wherein Q represents CH or N, Y represents substituted naphthalene, R⁶represents hydrogen atom or methyl, R⁷ represents hydrogen atom ormethyl, X represents substituted benzene, substituted naphthalene, orthe like (cf. the Publication for details of the symbols in theformula),can be used for therapy of incontinence of urine, overactive bladder,chronic pain, neurogenic pains, postoperative pain, and the like.

Furthermore, a pamphlet of International Publication No. 03/068749(Patent Document 3) describes that amide derivatives represented by thefollowing general formula:

X Y N CR⁹ NR⁸ C(R⁹)₂ CR⁹ N C(R⁹)₂ NR⁸wherein X and Y represent a combination described in the above table, Prepresents a phenyl or a heteroaryl or the like, R¹ and R² eachrepresents halo, alkyl, alkoxy, NR⁴R⁵, or the like, R³ represents alkyl,alkoxy, phenyl, or the like which may be substituted by R² group, q, r,and s each represents 0 to 3, and R⁴ and R⁵ each represents hydrogenatom, alkyl, or R⁴ and R⁵ together with the nitrogen atom form aheterocyclic ring (cf. the Publication for details of the symbols in theformula),can be used as an antagonist of VR1 for therapy and prevention ofvarious pains.

In the application, there are disclosed compounds wherein a combinationof P and R³ is biphenyl but, with regard to the compound wherein thebiphenyl ring contains further substituents R³, all the substituent arelow-molecular-weight groups such as lower alkyl groups, halogens, orsubstituted alkoxy groups.

On the other hand, there have been reported biphenylcarboxamidecompounds having a nitrogen-containing heterocycle, such as quinoline ortetrahydroquinoline on the amide nitrogen. For example, a pamphlet ofInternational Publication No. 01/21577 (Patent Document 4) and apamphlet of International Publication No. 03/035624 (Patent Document 5)describe tetrahydroquinoline derivatives and quinoline derivativeshaving an anti-obesity activity based on MCH receptor antagonism,respectively. Moreover, a pamphlet of International Publication No.98/41508 (Patent Document 6) and a pamphlet of International PublicationNo. 97/48683 (Patent Document 7) describe tetrahydroisoquinolinederivatives having anticonvulsant activity. However, all the compoundsare restricted to those having no substituent or onlylow-molecular-weight substituents on the biphenyl ring. Furthermore,there is neither disclosure nor suggestion on inhibitory activity of VR1receptor activation.

As mentioned above, a capsaicin receptor VR1 activation inhibitor isexpectable as a therapeutic agent for various pains includinginflammatory pains and neurogenic pains, migraine, cluster headache,bladder diseases including overactive bladder, and the like. It ishighly desired to develop a novel capsaicin receptor VR1 activationinhibitor which is different in chemical structure from the above knowncompounds and has a further excellent effect.

DISCLOSURE OF THE INVENTION

As a result of the extensive studies on compounds having an inhibitoryactivity of capsaicin receptor VR1 activation, the present inventorshave found that a compound represented by the following general formula(I) wherein a benzene ring is attached to a D ring (a monocyclic orbicyclic hydrocarbon ring or a monocyclic or bicyclic heteroaromaticring) through an amide bond, the benzene ring is directly bonded to an Ering (a monocyclic or bicyclic hydrocarbon ring or a monocyclic orbicyclic heteroaromatic ring), and the benzene ring is further bonded toA (an amino moiety, a monocyclic or bicyclic heterocycle) through L (alower alkylene) has an excellent inhibitory activity of VR1 activation.Thus, they have accomplished the present invention. Namely, theinvention relates to a compound represented by the following formula (I)and a salt thereof, and a medicament containing them as an activeingredient.

In this connection, the invention includes those wherein a cyclic grouprepresented by D is a nitrogen-containing bicyclic heterocycle such asquinoline or tetrahydroisoquinoline, however, the compound is differentin chemical structure from the specifically disclosed compoundsdescribed in Patent Document 3 in such a viewpoint that the benzene ringis bonded to A (an amino moiety, a monocyclic or bicyclic heterocycle)through L (a lower alkylene).

[1] A benzamide derivative represented by the following general formula(I):

wherein the symbols have the following meanings:A:

L: a lower alkylene,D ring and E ring: the same or different, a monocyclic or bicyclichydrocarbon ring, or a 5- to 12-membered monocyclic or bicyclicheteroaromatic ring containing 1 to 4 atoms of one or more kinds ofheteroatoms selected from the group consisting of N, S, and O,G ring: a 4- to 12-membered monocyclic or bicyclic heterocyclecontaining 1 to 4 atoms of one or more kinds of heteroatoms selectedfrom the group consisting of N, S, and O,R¹ to R⁹: the same or different, a hydrogen atom, a halogen atom, alower alkyl, a halogen-substituted lower alkyl, —OH, —SH, —O-loweralkyl, —O-lower alkyl-NH-lower alkyl, —O-lower alkyl-N(lower alkyl)₂,═O, —NH₂, —NH-lower alkyl, —N(lower alkyl)₂, —S-lower alkyl, —SO-loweralkyl, —SO₂-lower alkyl, —CN, —COOH, —C(═O)—O-lower alkyl, —C(═O)—NH₂,—C(═O)—NH-lower alkyl, —C(═O)—N(lower alkyl)₂, —NH—C(═O)-lower alkyl,—NH—SO₂-lower alkyl, —SO₂—NH₂, —SO₂—NH-lower alkyl, —C(═O)-lower alkyl,—NO₂ or a nitrogen-containing saturated heterocycle,R¹⁰: a hydrogen atom or a lower alkyl,R¹¹ to R¹⁵: the same or different, a hydrogen atom, a halogen atom, alower alkyl, a halogen-substituted lower alkyl, —OH, —O-lower alkyl,—S-lower alkyl, —SO-lower alkyl, —SO₂-lower alkyl, ═O, —C(═O)H,—C(═O)-lower alkyl, —COOH, —CN, —NH₂, —NH-lower alkyl, —N(lower alkyl)₂,—C(═O)—NH₂, —C(═O)—NH-lower alkyl, —C(═O)—N(lower alkyl)₂, —C(═O)-aryl,—C(═O)—NH-aryl, —NH—C(═O)-lower alkyl, —NH—C(═O)-aryl, —NH—SO₂-loweralkyl, —N(lower alkyl)-SO₂-lower alkyl, -lower alkylene-NH—SO₂-loweralkyl, -lower alkylene-NH—SO₂-aryl, —C(═O)—O-lower alkyl, -loweralkylene-OH, -lower alkylene-C(═O)—NH-lower alkyl, -loweralkylene-C(═O)—N(lower alkyl)₂, -lower alkylene-C(═O)—NH₂, -loweralkylene-C(═O)—OH, -lower alkylene-O-lower alkyl, -loweralkylene-S-lower alkyl, -lower alkylene-O—C(═O)-lower alkyl, -loweralkylene-NH-lower alkyl, -lower alkylene-N(lower alkyl)₂₁-loweralkylene-aryl, a cycloalkyl, an aryl, -(4- to 12-membered monocyclic orbicyclic heterocycle containing 1 to 4 atoms of one or more kinds ofheteroatoms selected from the group consisting of N, S, and O), —O-(4-to 12-membered monocyclic or bicyclic heterocycle containing 1 to 4atoms of one or more kinds of heteroatoms selected from the groupconsisting of N, S, and O), -lower alkylene-(4- to 12-memberedmonocyclic or bicyclic heterocycle containing 1 to 4 atoms of one ormore kinds of heteroatoms selected from the group consisting of N, S,and O), —C(═O)-(4- to 12-membered monocyclic or bicyclic heterocyclecontaining 1 to 4 atoms of one or more kinds of heteroatoms selectedfrom the group consisting of N, S, and O), -lower alkylene-N(loweralkyl)-(4- to 12-membered monocyclic or bicyclic heterocycle containing1 to 4 atoms of one or more kinds of heteroatoms selected from the groupconsisting of N, S, and O), or—C(═O)—NH-(4- to 12-membered monocyclic or bicyclic heterocyclecontaining 1 to 4 atoms of one or more kinds of heteroatoms selectedfrom the group consisting of N, S, and O), andthe above monocyclic or bicyclic heterocycle may be substituted byhalogen atom(s), lower alkyl(s), —O-lower alkyl, or —OH, and the sameshall apply hereinafter, or a salt thereof.[2] The compound according to the above [1], wherein the symbolsrepresented by D, E, R¹ to R⁹, and R¹¹ to R¹⁵ in the above formula (I)have the following meanings:D ring and E ring: the same or different, a benzene ring, a naphthalenering, or a 5- to 12-membered monocyclic or bicyclic heteroaromatic ringcontaining 1 to 4 atoms of one or more kinds of heteroatoms selectedfrom the group consisting of N, S, and O,R¹ to R⁹: the same or different, a hydrogen atom, a halogen atom, alower alkyl, a halogen-substituted lower alkyl, —OH, —SH, —O-loweralkyl, —O-lower alkyl-NH-lower alkyl, —O-lower alkyl-N(lower alkyl)₂,═O, —NH₂, —NH-lower alkyl, —N(lower alkyl)₂, —S-lower alkyl, —SO-loweralkyl, —SO₂-lower alkyl, —CN, —COOH, —C(═O)—NH₂, —C(═O)—NH-lower alkyl,—C(═O)—N(lower alkyl)₂, or —NH—C(═O)-lower alkyl,R¹¹ to R¹⁵: the same or different, a hydrogen atom, a halogen atom, alower alkyl, a halogen-substituted lower alkyl, —OH, —O-lower alkyl,—S-lower alkyl, —SO-lower alkyl, —SO₂-lower alkyl, ═O, —C(═O)H,—C(═O)-lower alkyl, —COOH, —CN, —NH₂, —NH-lower alkyl, —N(lower alkyl)₂,—C(═O)—NH₂, —C(═O)—NH-lower alkyl, —C(═O)—N(lower alkyl)₂, —C(═O)-aryl,—C(═O)—NH-aryl, —NH—C(═O)-lower alkyl, —NH—C(═O)-aryl, —NH—SO₂-loweralkyl, —N(lower alkyl)-SO₂-lower alkyl, —C(═O)—O-lower alkyl, -loweralkylene-O-lower alkyl, -lower alkylene-NH-lower alkyl, -loweralkylene-N(lower alkyl)₂, -lower alkylene-aryl, a cycloalkyl, an aryl, a4- to 12-membered monocyclic or bicyclic heterocycle containing 1 to 4atoms of one or more kinds of heteroatoms selected from the groupconsisting of N, S, and O, -lower alkylene-(4- to 12-membered monocyclicor bicyclic heterocycle containing 1 to 4 atoms of one or more kinds ofheteroatoms selected from the group consisting of N, S, and O),—C(═O)-(4- to 12-membered monocyclic or bicyclic heterocycle containing1 to 4 atoms of one or more kinds of heteroatoms selected from the groupconsisting of N, S, and O), -lower alkylene-N(lower alkyl)-(4- to12-membered monocyclic or bicyclic heterocycle containing 1 to 4 atomsof one or more kinds of heteroatoms selected from the group consistingof N, S, and O), or —C(═O)—NH-(4- to 12-membered monocyclic or bicyclicheterocycle containing 1 to 4 atoms of one or more kinds of heteroatomsselected from the group consisting of N, S, and O).

There may be mentioned the compound according to the following [3] as apreferred embodiment of the invention, the compounds according to thefollowing [4] to [9] as more preferred embodiments, and the compoundaccording to the following [10] as a particularly preferred embodiment.

[3] The compound according to the above [1], wherein the ringrepresented by E in the above formula (I) is a benzene or thiophenering, more preferably a benzene ring.

[4] The compound according to the above [3], wherein the compoundrepresented by A in the above formula (I) is the following formula:

[4a] More preferably, the compound according to the above [4], whereinthe ring represented by G in the above formula (I) is anitrogen-containing saturated heterocycle, more preferably a ringselected from tetrahydropyridine, tetrahydroquinoline,tetrahydroisoquinoline, piperidine, pyrrolidine, morpholine, azepane,and 1,4-oxazepane and the ring nitrogen atom is bonded to L.

[4b] More preferably, the compound according to the above [4], whereinthe ring represented by G in the above formula (I) is a ring selectedfrom morpholine, piperidine, and pyrrolidine and the ring nitrogen atomis bonded to L.

[4c] More preferably, the compound according to the above [4], whereinthe ring represented by D in the above formula (I) is a ring selectedfrom benzothiazole, quinoline, isoquinoline, indoline,tetrahydroquinoline, tetrahydroisoquinoline,3,4-dihydro-2H-1,4-benzoxazine, dihydroquinoline, anddihydroisoquinoline.

[4d] More preferably, the compound according to the above [4], furtherpreferably according to the above [4a], more further preferablyaccording to the above [4b], wherein the ring represented by D in theabove formula (I) together with the groups represented by R⁶ to R⁹ to bebonded thereto form a group selected from the following formulae:

wherein the symbols have the following meanings: R^(6a) and R^(6b): thesame or different, a hydrogen atom, a lower alkyl, or ahalogen-substituted lower alkyl, and R^(7a), R^(8a), R^(7b), and R^(8b):the same or different, a hydrogen atom, a halogen atom, a lower alkyl,or a halogen-substituted lower alkyl.

Or, the compound according to the above [4], further preferablyaccording to the above [4a], more further preferably according to theabove [4b], wherein the ring represented by D in the above formula (I)together with the groups represented by R⁶ to R⁹ to be bonded theretoform a group selected from the following formulae:

wherein the symbols have the following meanings:R^(6c) and R^(6d): the same or different, a hydrogen atom, a loweralkyl, or a halogen-substituted lower alkyl, and R^(7c), R^(8c), R^(7d),and R^(8d): the same or different, a hydrogen atom, a halogen atom, alower alkyl, or a halogen-substituted lower alkyl.

[4e] The compound according to the above [4], wherein at least one ofthe groups represented by R¹³ to R¹⁵ is a halogen atom, a lower alkyl, ahalogen-substituted lower alkyl, —OH, —O-lower alkyl, —NH₂, —N(loweralkyl)₂, —C(═O)—NH₂, —C(═O)—N(lower alkyl)₂, —NH—C(═O)-lower alkyl,—C(═O)—O-lower alkyl, -lower alkylene-O-lower alkyl, an aryl, a -(4- to12-membered monocyclic or bicyclic heterocycle containing 1 to 4 atomsof one or more kinds of heteroatoms selected from the group consistingof N, S, and O), or -lower alkylene-(4- to 12-membered monocyclic orbicyclic heterocycle containing 1 to 4 atoms of one or more kinds ofheteroatoms selected from the group consisting of N, S, and O), and theother is a hydrogen atom. More preferably, the compound according to theabove [4], wherein at least one of the symbols represented by R¹³ to R¹⁵is a lower alkyl, —O-lower alkyl, —N(lower alkyl)₂, -(4- to 12-memberedmonocyclic or bicyclic heterocycle containing 1 to 4 atoms of one ormore kinds of heteroatoms selected from the group consisting of N, S,and O), or -lower alkylene-(4- to 12-membered monocyclic or bicyclicheterocycle containing 1 to 4 atoms of one or more kinds of heteroatomsselected from the group consisting of N, S, and O) and the other is ahydrogen atom.

[5] The compound according to the above [3], wherein the grouprepresented by A in the above formula (I) is the following formula:

wherein the symbols have the following meanings:R^(11a) and R^(12a): the same or different, a hydrogen atom, a loweralkyl, a halogen-substituted lower alkyl, —O-lower alkyl, —SO₂-loweralkyl, —C(═O)H, —C(═O)-lower alkyl, —CN, —NH₂, —NH-lower alkyl, —N(loweralkyl)₂, —C(═O)—NH₂, —C(═O)—NH-lower alkyl, —C(═O)—N(lower alkyl)₂,—C(═O)-aryl, —C(═O)—NH-aryl, —NH—C(═O)-lower alkyl, —NH—C(═O)-aryl,—NH—SO₂-lower alkyl, —N(lower alkyl)-SO₂-lower alkyl, -loweralkylene-NH—SO₂-lower alkyl, -lower alkylene-NH—SO₂-aryl, —C(═O)—O-loweralkyl, -lower alkylene-OH, -lower alkylene-C(═O)—NH-lower alkyl, -loweralkylene-C(═O)—N(lower alkyl)₂, -lower alkylene-C(═O)—NH₂, -loweralkylene-C(═O)—OH, -lower alkylene-O-lower alkyl, -loweralkylene-5-lower alkyl, -lower alkylene-O—C(═O)-lower alkyl, -loweralkylene-NH-lower alkyl, -lower alkylene-N(lower alkyl)₂, -loweralkylene-aryl, a cycloalkyl, an aryl, -(4- to 12-membered monocyclic orbicyclic heterocycle containing 1 to 4 atoms of one or more kinds ofheteroatoms selected from the group consisting of N, S, and O), —O-(4-to 12-membered monocyclic or bicyclic heterocycle containing 1 to 4atoms of one or more kinds of heteroatoms selected from the groupconsisting of N, S, and O), -lower alkylene-(4- to 12-memberedmonocyclic or bicyclic heterocycle containing 1 to 4 atoms of one ormore kinds of heteroatoms selected from the group consisting of N, S,and O), —C(═O)-(4- to 12-membered monocyclic or bicyclic heterocyclecontaining 1 to 4 atoms of one or more kinds of heteroatoms selectedfrom the group consisting of N, S, and O), -lower alkylene-N(loweralkyl)-(4- to 12-membered monocyclic or bicyclic heterocycle containing1 to 4 atoms of one or more kinds of heteroatoms selected from the groupconsisting of N, S, and O), or —C(═O)—NH-(4- to 12-membered monocyclicor bicyclic heterocycle containing 1 to 4 atoms of one or more kinds ofheteroatoms selected from the group consisting of N, S, and O), and

the above monocyclic or bicyclic heterocycle may be substituted byhalogen atom(s), lower alkyl(s), —O-lower alkyl, or —OH.

[5a] The compound according to the above [5], wherein R^(11a) is a loweralkyl and R^(12a) is a group selected from -lower alkylene-O-loweralkyl, -lower alkylene-S-lower alkyl, -lower alkylene-NH-lower alkyl,-lower alkylene-N(lower alkyl)₂, -lower alkylene-OH, -loweralkylene-C(═O)—NH-lower alkyl, -lower alkylene-C(═O)—N(lower alkyl)₂,-lower alkylene-aryl, a cycloalkyl, an aryl, -(4- to 12-memberedmonocyclic or bicyclic heterocycle containing 1 to 4 atoms of one ormore kinds of heteroatoms selected from the group consisting of N, S,and O), and -lower alkylene-(4- to 12-membered monocyclic or bicyclicheterocycle containing 1 to 4 atoms of one or more kinds of heteroatomsselected from the group consisting of N, S, and O).

[5b] More preferably the compound according to the above [5], whereinthe ring represented by D in the above formula (I) is a ring selectedfrom benzothiazole, quinoline, isoquinoline, indoline,tetrahydroquinoline, tetrahydroisoquinoline,3,4-dihydro-2H-1,4-benzoxazine, dihydroquinoline, anddihydroisoquinoline.

[5c] More preferably, the compound according to the above [5], morepreferably the compound according to the above [5a], wherein the ringrepresented by D in the above formula (I) together with the groupsrepresented by R⁶ to R⁹ to be bonded thereto form a group selected fromthe following formulae:

wherein the symbols have the following meanings:R^(6a) and R^(6b): the same or different, a hydrogen atom, a loweralkyl, or a halogen-substituted lower alkyl, and R^(7a), R^(8a), R^(7b),and R^(8b): the same or different, a hydrogen atom, a halogen atom, alower alkyl, or a halogen-substituted lower alkyl.

Or, the compound according to the above [5], more preferably thecompound according to the above [5b], wherein the ring represented by Din the above formula (I) together with the groups represented by R⁶ toR⁹ to be bonded thereto form a group selected from the followingformulae:

wherein the symbols have the following meanings:R^(6c) and R^(6d): the same or different, a hydrogen atom, a loweralkyl, or a halogen-substituted lower alkyl, and R^(7c), R^(8c), R^(7d),and R^(8d): the same or different, a hydrogen atom, a halogen atom, alower alkyl, or a halogen-substituted lower alkyl.[6] The compound according to the above [1], wherein R¹ to R⁵ are thesame or different and each is a hydrogen atom, a halogen, ahalogen-substituted lower alkyl, a lower alkyl, —N(lower alkyl)₂, or—O-lower alkyl.[7] The compound according to the above [1], wherein R⁶ to R⁹ are thesame or different and each is a hydrogen atom, a halogen atom, a loweralkyl, a halogen-substituted lower alkyl, —OH, —O-lower alkyl, ═O,—NH-lower alkyl, —N(lower alkyl)₂, —CN, —C(═O)—NH₂, —NH—SO₂-lower alkyl,—SO₂—NH₂, —C(═O)-lower alkyl, —NO₂, or a nitrogen-containing saturatedheterocycle, more preferably, a hydrogen atom, a halogen, ahalogen-substituted lower alkyl, a lower alkyl, —OH, ═O, —N(loweralkyl)₂, or —SO₂—NH₂. Further preferably, the compound according to theabove [1], wherein R⁶ to R⁸ are the same or different and each is ahydrogen atom, a halogen atom, a lower alkyl, or a halogen-substitutedlower alkyl and R⁹ is ═O.[8] The compound according to the above [1], wherein R¹⁰ in the aboveformula (I) is a hydrogen atom.[9] The compound according to the above [1], wherein the grouprepresented by L is methylene or ethylene, more preferably methylene.[10] The compound according to the above [1] or a salt thereof, whereinthe benzamide derivative represented by the above formula (I) is atleast one compound selected from the group consisting ofN-1,3-benzothiazol-5-yl-2-{[cyclohexyl(isopropyl)amino]methyl}biphenyl-4-carboxamide,N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-2-(piperidin-1-ylmethyl)biphenyl-4-carboxamide,N-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-(piperidin-1-ylmethyl)biphenyl-4-carboxamide,2-{[ethyl(2-hydroxy-2-methylpropyl)amino]methyl}-N-(2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)biphenyl-4-carboxamide,N-(1-methyl-2-oxo-1,2-dihydroquinolin-7-yl)-2-(piperidin-1-ylmethyl)biphenyl-4-carboxamide,N-(3-methyl-2-oxo-1,2-dihydroquinolin-7-yl)-2-(piperidin-1-ylmethyl)biphenyl-4-carboxamide,N-(2,4-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-2-(piperidin-1-ylmethyl)biphenyl-4-carboxamide,2-{[ethyl(tetrahydro-2H-pyran-4-yl)amino]methyl}-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)biphenyl-4-carboxamide,N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-3-(piperidin-1-ylmethyl)-4-(2-thienyl)benzamide,2-{[ethyl(tetrahydro-2H-thiopyran-4-yl)amino]methyl}-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)biphenyl-4-carboxamide,2-{[isobutyl(2-piperidin-1-ylethyl)amino]methyl}-N-(2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)biphenyl-4-carboxamide,N,N-diethyl-4-[(4-{[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino]carbonyl}biphenyl-2-yl)methyl]morpholine-3-carboxamide,and2-[(4-methyl-1,3′-bipiperidin-1′-yl)methyl]-N-(2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-yl)biphenyl-4-carboxamide.

Moreover, the invention relates to a pharmaceutical compositioncomprising a benzamide derivative represented by the above formula (I)or a salt thereof and pharmaceutically acceptable carrier. Preferably,it is the aforementioned pharmaceutical composition, which is a VR1activation inhibitor and more preferably, it is the aforementionedpharmaceutical composition, which is a preventive or therapeutic agentfor pains.

Furthermore, the other embodiments include use of a benzamide derivativerepresented by the general formula (I) according to [1] to [10] or asalt thereof for manufacturing a preventive or therapeutic agent forpains and a method for preventing or treating pain, comprisingadministering an effective amount of a benzamide derivative representedby the general formula (I) according to [1] to [10] or a salt thereof.

The following will describe the invention in detail.

The “capsaicin receptor VR1 activation inhibitor” herein is a genericname of both compounds (VR1 antagonist) which bind to the VR1 receptorand inhibit VR1 activation by competition with an endogenous ligand andcompounds (VR1 agonist) which desensitize nerves where the receptor ispresent and inhibit their subsequent activation by continuous activationof the VR1 receptor. As the “VR1 activation inhibitor”, a VR1 antagonistis preferable.

In the definition of the general formulae herein, the term “lower” meansa linear or branched carbon chain having from 1 to 6 carbon atoms,unless otherwise specified. Therefore, the “lower alkyl” is preferablyalkyl having 1 to 5 carbon atoms, and particularly preferred are methyl,ethyl, propyl, isopropyl, butyl, isobutyl, and 1,2-dimethylpropyl. Asthe “lower alkylene”, preferred are linear alkylenes such as methylene,ethylene, propylene, and butylene, and branched alkylenes such asmethylmethylene. Particularly preferred are methylene and ethylene.

The “halogen atom” includes fluorine, chlorine, bromine, and iodineatoms. Particularly, a fluorine atom and a chlorine atom are preferred.The “halogen-substituted lower alkyl” means a group wherein the abovelower alkyl is substituted by 1 to 3 halogens which are the same ordifferent. Particularly, trifluoromethyl is preferred.

As the “monocyclic or bicyclic hydrocarbon ring”, there may be mentionedbenzene, naphthalene, cycloalkyl rings having 3 to 8 ring members,cycloalkenyl rings having 4 to 8 ring members, and saturated hydrocarbonring-condensed aryl rings wherein a cycloalkyl or a cycloalkenyl ring isfused to benzene. Preferred are benzene, naphthalene, indane, andtetrahydronaphthalene.

The “aryl” is an aryl having 6 to 14 carbon atoms, and is furtherpreferably phenyl or naphthyl.

The “cycloalkyl” is preferably a cycloalkyl group having 3 to 10 carbonatoms which may possess brige(s), and further preferred are cyclopropyl,cyclopentyl, cyclohexyl, cycloheptyl, and adamantyl groups.

The “nitrogen-containing saturated heterocycle” is a 5- to 8-memberedsaturated or partially unsaturated monocyclic heterocycle which containsone N atom and may further contain one heteroatom selected from N, S,and O, and preferred are pyrrolidine, piperidine, piperazine, azepane,diazepane, morpholine, thiomorpholine, and tetrahydropyridine rings.

The “5- to 12-membered monocyclic or bicyclic heteroaromatic ringcontaining 1 to 4 atoms of one or more kinds of heteroatoms selectedfrom the group consisting of N, S, and O” is a 5- to 6-memberedmonocyclic heteroaromatic ring containing 1 to 4 atoms of heteroatomsselected from the group consisting of N, S, and O and a bicyclicheteroaryl group wherein this monocyclic heteroaromatic ring iscondensed with a benzene ring or a 5- to 6-membered monocyclicheteroaromatic ring. These rings may be partially saturated. Moreover,in the case that an N atom or an S atom is included in the ring atoms,the atom may form an oxide or a dioxide. As the 5- to 6-memberedmonocyclic heteroaromatic ring, preferred are pyridine, pyrimidine,pyrazine, pyridazine, triazine, pyrrole, furan, thiophene, thiazole,imidazole, oxazole, isothiazole, pyrazole, isozazole, thiadiazole,triazole, and tetrazole rings. As the bicyclic heterocycle, preferredare benzothiazole, benzoisothiazole, benzoxazole, benzisoxazole,benzimidazole, benzotriazole, benzothiadiazole, benzoxadiazole,quinoline, isoquinoline, naphthylidine, quinoxaline, quinazoline,phthalazine, cinnoline, indole, indazole, imidazopyridine,benzothiophene, benzothiophene-1,1-dioxide, benzofuran,dihydrobenzofuran, dihydro-1,3-benzoxazole, dihydro-1,3-benzothiazole,1,3-benzodioxole, benzazepine, benzodiazepine, benzoxazine,tetrahydrobenzoxazepine, tetrahydrobenzazepine, tetrahydroquinoline,tetrahydroisoquinoline, tetrahydronaphthopyridine,tetrahydroquinoxaline, chroman, dihydrobenzodioxine,3,4-dihydro-2H-1,4-benzothiazine, dihydrobenzothiazole,3,4-dihydro-2H-1,4-benzoxazine, isochroman, indoline, and pteridinerings. Further preferred are pyridine, benzothiazole, benzoxazole,quinoline, isoquinoline, dihydroquinoline, dihydroisoquinoline,indoline, tetrahydroquinoline, tetrahydroisoquinoline, benzothiophene,3,4-dihydro-2H-1,4-benzoxazine, 3,4-dihydro-2H-1,4-benzothiazine, anddihydro-1,3-benzoxazole rings.

The “4- to 12-membered monocyclic or bicyclic heterocycle containing 1to 4 atoms of one or more kinds of heteroatoms selected from the groupconsisting of N, S, and O” is, in addition to the above monocyclic orbicyclic heteroaromatic rings, a 4- to 8-membered saturated or partiallyunsaturated monocyclic heterocycle, and a bicyclic heterocycle obtainedby condensing it with a cycloalkyl ring, a cycloalkenyl ring, or asaturated or partially unsaturated monocyclic heterocycle. Preferred aresaturated or partially unsaturated monocyclic heterocycles such aspyrrolidine, imidazolidine, pyrazolidine, quinuclidine, piperidine,piperazine, morpholine, thiomorpholine, thiomorpholine 1,1-dioxide,azepane, azocane, 1,4-ozazepane, azetidine, 1,2,3,6-tetrahydropyridine,and imidazoline, and saturated or partially unsaturated bicyclicheterocycles such as decahydroquinoline and decahydroisoquinoline. Morepreferred are nitrogen-containing saturated heterocycles and furtherpreferred are pyrrolidine, piperidine, piperazine, and morpholine rings.

In the case that the substituent is described as R^(7a) or R^(8a) in thefollowing formula, it shows that the substituent may be bonded to acarbon atom on any of left and right rings.

Moreover, among the compounds of the invention, there exist geometricalisomers, tautomers, and optical isomers depending on the kind ofsubstituents. The invention encompasses mixtures of such isomers andthose isolated.

The compounds of the invention form acid addition salts in some cases.Also, they form salts with bases in some cases. Specifically, such saltsinclude addition salts with inorganic acids such as hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, andphosphoric acid; or with organic acids such as formic acid, acetic acid,propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid,maleic acid, lactic acid, malic acid, tartaric acid, citric acid,methanesulfonic acid, ethanesulfonic acid, aspartic acid, and glutamicacid; the salts with inorganic bases such as sodium, potassium,magnesium, calcium, and aluminum; with organic bases such asmethylamine, ethylamine, ethanolamine, lysine and ornithine; ammoniumsalts; and the like.

Furthermore, the invention encompasses hydrates of the compounds of theinvention, pharmaceutically acceptable various solvates, compoundshaving crystalline polymorphism, and the like.

The compounds of the invention also include compounds which aremetabolized in a living body to be converted into the compoundrepresented by the above general formula (I) or salts thereof, so-calledprodrugs. The groups that form the prodrugs of the compounds of theinvention are groups described in Prog. Med. 5:2157-2161 (1985) andgroups described in “Iyakuhinn no Kaihatsu (Development of Medicines)published by Hirokawa Shoten, 1990, Vol. 7, Bunshi Sekkei (MolecularDesign), pp. 163-198.

(Production Methods)

The following will describe representative methods of the compounds ofthe invention.

In this connection, in the following production process, depending onthe kind of functional groups, it is sometimes technically effective toreplace the functional groups to suitable protective groups at a stageof starting materials or intermediates, i.e., groups easily convertibleinto the functional groups. Thereafter, the protective groups can beremoved to obtain desired compound when required. As such functionalgroups, there may be, for example, an amino group, a hydroxyl group, acarboxyl group, and the like. As such protective groups, there can bementioned protective groups described in Protective Groups in OrganicSynthesis 3rd edition (written by T. W. Green and P. G. M. Wuts,published by JOHN WILLY & SONS, INC), which may be suitably useddepending on the reaction conditions. The method described in saidreference can be applicable to introduction and removal of theprotective groups.

(Production Method 1)

The production method 1 is a reaction of synthesizing a compound (I) bya condensation reaction of a carboxylic acid with an amine using acompound (II) and a compound (III).

The present reaction may be carried out according to a usual methodusing the compound (II) and the amine derivative (III) in equimolaramounts or in an excess of one of them in the presence of a condensingagent. As the condensing agent, there can be suitably usedN,N-dicyclohexylcarbodiimide (DCC),1-ethyl-3-[3-(N,N-dimethylamino)propyl]carbodiimide,O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), carbonyldiimidazole, diphenylphosphoryl azide (DPPA),diethylphosphoryl cyanide, or the like. These condensing agents are usedin an equimolar amount or in an excess amount of carboxylic acid. As asolvent, there can be used a solvent which does not participate in thereaction, N,N-dimethylformamide (DMF), dioxane, tetrahydrofuran, ether,dichloroethane, dichloromethane, chloroform, carbon tetrachloride,dimethoxymethane, dimethoxyethane, ethyl acetate, benzene, acetonitrile,dimethyl sulfoxide, or a mixed solvent thereof, and the solvent issuitably selected according to the applying method. Moreover, dependingon the applying method, there is a case that the reaction easilyproceeds by carrying out the reaction in the presence of a base such asN-methylmorpholine, triethylamine, trimethylamine, pyridine, or4-dimethylaminopyridine or using the base as a solvent. Usually, theabove reaction is carried out under cooling to under room temperaturebut it is sometimes preferred that the reaction is carried out under anelevated temperature depending on the kind of acylation reaction.

Moreover, the compound (I) can be also produced by the method ofintroducing a carboxylic acid into an active derivative and thencondensing the resulting product with an amine. In this case, thereaction is carried out using the compound (II) and the amine derivative(III) in equimolar amounts or in an excess of one of them. As the activederivative of the carboxylic acid, there may be mentioned an activeester obtained by reacting the acid with a phenolic compound such asp-nitrophenol or an N-hydroxyamine compound such as 1-hydroxysuccinimideor 1-hydroxybenzotriazole, a monoalkylcarbonate, a mixed anhydrideobtained by reacting it with an organic acid, a phosphate type mixedanhydride obtained by reacting it with diphenylphosphoryl chloride andN-methylmorpholine, an acid azide obtained by successively reacting anester with hydrazine and alkyl nitrite, an acid halide such as an acidchloride or an acid bromide, and a symmetric acid anhydride. Thereaction is carried out using an activation reagent in an equimolaramount to the compound (II) or in an excess thereof relative to thecompound. The reaction conditions in this case are also the same asthose in the case using the condensing agent.

Moreover, other than the reactions described above, any reactions can beused as far as they form amide bonds.

(Production Method 2)

wherein X means a leaving group such as —Cl, —Br, —I,methanesulfonyloxy, or toluenesulfonyloxy, and the same shall applyhereinafter.

The production method 2 is a reaction of synthesizing the compound (I)by a nucleophilic substitution reaction using a compound (IV) and anamine compound A-H.

The present reaction is carried out using the compound (IV) and A-H inequimolar amounts or in an excess of one of them under ice cooling tounder an elevated temperature by adding a base (preferably, potassiumcarbonate, sodium carbonate, sodium hydrogen carbonate, potassiumtert-butoxide, triethylamine, pyridine, N-methylmorpholine, sodiumhydroxide) using the solvent described in the production method 1 as asolvent.

In the case that the compounds (I) of the invention have various sidechains and functional groups, these compounds can be easily synthesizedusing the compounds of the invention or production intermediates thereofas starting materials by means of reactions obvious for those skilled inthe art or modified method thereof. As such examples, there may bementioned conversion of any of R¹ to R⁹ of the compound (I) obtained bythe production method 1 or conversion of newly introducing it. Forexample, the following reactions can be applied.

The compound wherein any substituent of R¹ to R⁹ in the formula (I) is—SO₂—NH₂ or CO—NH₂ can be produced using a compound wherein each of thecorresponding R¹ to R⁹ is —SO₃H or CO₂H. The reaction is carried out bycondensing —SO₃H or CO₂H of R¹ to R⁹ with ammonia under the sameconditions as those in the first production reaction.

Moreover, the compound wherein the D ring in the formula (I) is asaturated ring and any substituent of R¹ to R⁹ in the formula (I) is —OHcan be produced using a compound wherein the present substituent is acarbonyl group by applying a usual method for a reduction reaction. Forexample, the reaction can be carried out with referring to the methoddescribed in Tetrahedron, 35, 567-607 (1979).

Furthermore, the compound wherein the D ring or the E ring is aheterocycle and a heteroatom in the ring is oxidized into an oxide canbe synthesized by oxidizing the heteroatom using a usual method for theoxidation reaction. The reaction can be carried out with referring tothe method described in J. Hetrocycl. Chem. 19, 237-240, (1982), J.Chem. Soc. Perkin Trans. 1, 1949-1955, (1984).

(Production Method of Starting Materials)

The following will describe representative production methods for thestarting materials described in the production method 1 and theproduction method 2.

(1) Starting Compound (II)

The first step to the eleventh step show production steps for producingthe starting material (II) in the production method 1.

wherein any one of U and Q is —Br, —Cl, —I, or —O—SO₂—CF₃ and anotherone means —B(OH)₂ or —B(O-lower alkyl)₂, P¹ means a protective group ofcarboxyl, such as a methyl group, an ethyl group, a benzyl group, or atert-butyl group and X¹ means —Cl, —Br, or —I, and the same shall applyhereinafter.

First, the first step is a step of producing a compound (VII) by across-coupling reaction using a compound (V) and a compound (VI). Thereaction can be carried out with referring to the method described inSynth. Commun., 11, 513-519 (1981), Synlett 2000, No. 6, 829-831, andChem. lett., 1989, 1405-1408.

The second step is a step of producing (VIII) by treating the compound(VII) with a halogenating agent. The reaction is carried out under roomtemperature to under reflux with heating using N-bromosuccinimide (NBS),bromine, sulfuryl chloride, or copper bromide as a halogenating agent ina solvent such as carbon tetrachloride, chloroform, or benzene, withadding benzoyl peroxide, 2,2′-azobisisobutyronitrile, tert-butylhydroperoxide, or tetrakistriphenylphosphine palladium or underirradiation with light, if necessary.

The third step is a step of producing a compound (IXa) by removing theprotective group P¹ of the compound (VIII) and simultaneouslyhydrolyzing the X¹ group. The present reaction may be carried outfollowing a usual method for basic hydrolysis of halides. However, inthe case that the protective group is not deprotected by hydrolysis witha base, after the hydrolysis of the X¹ group of the compound (VIII), thedeprotection reaction may be carried out by hydrolysis with an acid suchas hydrochloric acid or trifluoroacetic acid or by reduction such ascatalytic hydrogenation. The reaction conditions may be used accordingto the aforementioned “Protective Groups in Organic Synthesis”.

The fourth step is a step of producing a compound (X) by an oxidationreaction of the compound (VIII). The reaction is carried out using anoxidizing agent such as N-methylmorpholine-N-oxide,trimethylamine-N-oxide, sodium salt of 2-nitropropane described in J.Am. Chem. Soc., 71, 1767-1769 (1949), or silver nitrate, in a solventsuch as acetonitrile or ethanol under ice cooling to under reflux.

The fifth step is a step of producing a compound (XI) from the compound(X). The reaction is carried out using(methoxymethyl)triphenylphosphonium chloride,(methoxymethyl)triphenylphosphonium bromide, or the like as a reactingagent in the presence of a base such as n-butyllithium,sec-butyllithium, sodium hydride, or potassium tert-butoxide in asolvent such as tetrahydrofuran, diethyl ether, or cyclopentyl methylether under −78° C. to under an elevated temperature.

The sixth step is a step of producing a compound (XIIa) by condensingthe compound (XI) with A-H by a reductive amination reaction. Thereaction is carried out using sodium triacetoxyborohydride, sodiumborohydride, or the like as a reducing agent, with adding an organicacid (preferably, acetic acid, formic acid, or p-toluenesulfonic acid),a Lewis acid such as a metal salt (preferably, tetraisopropoxytitanium),if necessary. The reaction is carried out using a solvent such asdichloromethane, dichloroethane, chloroform, carbon tetrachloride, ortetrahydrofuran under ice cooling to under an elevated temperature.

The seventh step and the eighth step are steps of producing compounds(XIIIa) and (XIIIb) by reducing the formyl group of the compounds (X)and (XI), respectively. The reaction can be carried out with referringto the method described in Tetrahedron, 35, 567-607 (1979).

The ninth step is a step of producing a compound (XIVa) by halogenatingthe hydroxyl group of the compound (XIIIb) or by converting it into asulfonate ester. The halogenation is carried out using an acid halide(preferably, thionyl chloride, phosphorus trichloride, phosphoruspentachloride, phosphorus oxychloride, or phosphorus tribromide, etc.)or using triphenylphosphine and carbon tetrachloride, triphenylphosphineand carbon tetrabromide, or the like. The conversion into a sulfonateester is carried out by treating it with methanesulfonyl chloride orp-toluenesulfonyl chloride in the presence of a base (preferably,triethylamine, pyridine, or potassium carbonate). It is carried outusing dichloroethane, methylene chloride, chloroform, dioxane, or hexaneas a solvent under ice cooling to under reflux with heating. Moreover,by treating the resulting chloride, bromide, or sulfate ester withsodium iodide, potassium iodide, or the like, an iodide can be alsoobtained. As a solvent in this case, acetone, 2-butanone, ethanol, orthe like is used.

By applying the same reaction conditions as those of the ninth step tothe compound (XIIIa), the hydroxyl group of the compound (XIIIa) can behalogenated or converted into a sulfonate ester.

The tenth step is a step of producing a compound (XII) by reacting thecompound (VIV) with A-H. The reaction is carried out under the sameconditions as those of the production method 2.

The eleventh step is a step of producing the compound (II) by removingthe protective group P¹ of the compound (XII). The deprotection reactionmay be preferably carried out using procedures described in theaforementioned “Protective Groups in Organic Synthesis”.

(2) Starting Compound (IV)

The twelfth to fifteenth steps show how to produce the starting compound(IV) in the production method 2.

First, the compound (IV) can be produced by sequentially carrying outthe twelfth and fifteenth steps. The reaction can be carried out bycondensing the compound (IX) and the compound (III) in the same manneras in the production method 1 and then halogenating the hydroxyl groupof the resulting compound (XV) or by converting it into a sulfonateester as in the ninth step.

Moreover, it is possible to produce a compound in the formula (IV)wherein X is restricted to X¹, namely a compound (IVa) via thethirteenth step and the fourteenth step. Namely, by treating thecompound (IX) under the halogenation reaction conditions according tothe ninth step, halogenation of the hydroxyl group and conversion of thecarboxyl group into an acid halide are simultaneously carried out and anamide bond may be formed by reacting the resulting acid halide (XVI)with the amine derivative (III) separately prepared. The reaction iscarried out in dichloroethane, methylene chloride, or the like in thepresence of a base (pyridine, triethylamine, potassium carbonate, orsodium hydrogen carbonate) under cooling to under room temperature butunder an elevated temperature depending on the kind of acyl reactions.

Furthermore, it is also possible to synthesize the compound (IV) byremoving the protective group P¹ of the compound (XIV) and condensingthe resulting carboxylic acid with the amine compound (III) under thesame conditions as those of the production method 1.

The compounds of the invention thus produced may be isolated andpurified, as free compounds or their salts, by applying usual chemicaloperations such as extraction, precipitation, fractional chromatography,fractional crystallization, and recrystallization. Salts of thecompounds can be produced by treating the free compounds to an ordinarysalt formation.

Moreover, in the case that the compound of the invention has anasymmetric carbon, optical isomers are present. These optical isomerscan be produced by methods of leading them to diastereomeric salts withan optically active acid or base, followed by fractionalcrystallization, optical resolution by a usual method such as columnchromatography, or synthesis using an optically active startingmaterial.

BEST MODE FOR CARRYING OUT THE INVENTION Examples

The following will explain the process for producing the compound of theinvention specifically with reference to the following Examples. In thisconnection, processes for producing starting materials are shown asReference Examples.

Reference Example 1

Into 150 ml of water were suspended 55.9 g of sodium carbonate and 38.6g of phenylboronic acid. Thereto was added 51.4 g of ethyl4-bromo-3-methylbenzoate dissolved in 400 ml of toluene and then wasadded 4.0 g of tetrakistriphenylphosphine palladium, followed by 2 hoursof reflux with heating. After the reaction solution was cooled to roomtemperature, filtration was conducted using celite, water was added tothe filtrate and the organic layer was extracted with toluene. After theorganic layer was dried over anhydrous magnesium sulfate, the solventwas removed by evaporation and the resulting residue was purified bysilica gel column chromatography (hexane:ethyl acetate) to obtain 50.4 gof ethyl 2-methylbiphenyl-4-carboxylate as a colorless oil.

Reference Example 2

In 130 ml of carbon tetrachloride was dissolved 10 g of2-methylbiphenyl-4-carboxylate, the whole was heated to 90° C. and then1.0 g of NBS and 136 mg of 2,2′-azobisisobutyronitrile were addedthereto. After the reaction solution was heated under reflux, 6.78 g ofNBS was added thereto and the whole was heated under reflux for 1 hourand a half. After the reaction solution was cooled to room temperature,precipitate was removed by filtration, water was added to the filtrate,and the organic layer was extracted with carbon tetrachloride. After theresulting organic layer was dried over anhydrous magnesium sulfate, thesolvent was removed by evaporation to obtain 13.6 g of ethyl2-(bromoethyl)biphenyl-4-carboxylate as a white solid.

Reference Example 3

In 50 ml of DMF was dissolved 13.6 g of ethyl2-(bromoethyl)biphenyl-4-carboxylate, and then a suspension of 50 ml ofDMF, 6.2 ml of piperidine, and 9.2 g of potassium carbonate were addedthereto under ice cooling, followed by 3 hours of stirring at roomtemperature. Water was added to the reaction solution, the whole wasextracted with ethyl acetate, and the resulting organic layer was driedover anhydrous magnesium sulfate, followed by removal of the solvent byevaporation. The obtained residue was purified by silica gel columnchromatography (chloroform:methanol:aqueous ammonia) to obtain 12.6 g ofethyl 2-(piperidin-1-ylmethyl)biphenyl-4-carboxylate as a pale yellowoil.

Reference Examples 4 to 16

The compounds of Reference Examples 4 to 16 shown in the following Tablewere obtained in the same manner as in Reference Example 3.

Reference Example 17

In 150 ml of ethanol was dissolved 11 g of ethyl2-(piperidin-1-ylmethyl)biphenyl-4-carboxylate, and then 51 ml of a 1Maqueous sodium hydroxide was added thereto under ice cooling, followedby 10 hours of stirring at room temperature. Under ice cooling, 51 ml ofa 1M aqueous hydrochloric acid was added to the reaction solution andthen the solvent was removed by evaporation to obtain 12.6 g of a palepink solid which was a mixture of2-(piperidin-1-ylmethyl)biphenyl-4-carboxylic acid and 1.5 equivalentsof sodium chloride.

Reference Examples 18 to 40

The compounds of Reference Examples 18 to 30 shown in the followingTables were obtained in the same manner as in Reference Example 17.

The compounds of Reference Examples 31 to 35 shown in the followingTable were obtained in the same manner as in Reference Example 3.

The compounds of Reference Examples 36 to 40 shown in the followingTable were obtained in the same manner as in Reference Example 17.

Reference Example 41

In 100 ml of acetonitrile was dissolved 9.3 g of ethyl2-(bromomethyl)biphenyl-4-carboxylate, and 7.0 g ofN-methylmorpholine-N-oxide was added thereto at room temperature,followed by 4 hours of stirring. Water was added to the reactionsolution, which was then extracted with ethyl acetate. The resultingorganic layer was dried over anhydrous magnesium sulfate. After thesolvent was removed by evaporation, the obtained residue was purified bysilica gel column chromatography (hexane:ethyl acetate) to obtain 4.94 gof ethyl 2-formylbiphenyl-4-carboxylate as a white solid.

Reference Example 42

A suspension of 17.1 g of (methoxymethyl)triphenylphosphonium chloridein 150 ml of tetrahydrofuran was cooled to −78° C. and a 1.59M hexanesolution of n-butyllithium was added dropwise to the suspension,followed by 30 minutes of stirring. Further, after the reaction solutionwas warmed to −40° C. and stirred for 10 minutes, it was again cooled to−78° C. and 4.2 g of ethyl 2-formylbiphenyl-4-carboxylate dissolved in20 ml of tetrahydrofuran was added dropwise over a period of 20 minutes.The reaction solution was warmed from −50° C. to 10° C. over a period of12 hours, followed by 4 hours of stirring at room temperature. Thereaction solution was subjected to removal by evaporation, and ethylacetate and water were added to the residue, followed by separation ofan organic layer. The organic layer was dried over anhydrous magnesiumsulfate, the solvent was removed by evaporation, and the obtainedresidue was purified by silica gel column chromatography (hexane:ethylacetate) to obtain 1.66 g of a colorless oil. The substance wasdissolved in 50 ml of 1,2-dichloroethane and 25 ml of formic acid wasadded thereto at room temperature, followed by 51 hours of stirring.Water and ethyl acetate were added to the reaction solution, anoperation for separation was conducted, and the resulting organic layerwas dried over anhydrous magnesium sulfate. After the solvent wasremoved by evaporation, the residue was purified by silica gel columnchromatography (hexane:ethyl acetate) to obtain 1.06 g of ethyl2-(2-oxoethyl)biphenyl-4-carboxylate as a white solid.

Reference Example 43

In 20 ml of 1,2-dichloroethane was dissolved 1.06 g of ethyl2-(2-oxoethyl)biphenyl-4-carboxylate, and then 3.95 ml of piperidine,589 μl of acetic acid, and 1.09 g of sodium triacetoxyborohydride wereadded thereto, followed by 3 hours of stirring. Water and chloroformwere added to the reaction solution, and the organic layer obtained byan operation of separation was dried over anhydrous magnesium sulfate,followed by removal of the solvent by evaporation. The obtained residuewas purified by silica gel column chromatography(chloroform:methanol:aqueous ammonia) to obtain 1.3 g of oily ethyl2-(piperidin-1-ylethyl)biphenyl-4-carboxylate.

Reference Example 44

The compound of Reference Example 44 shown in the following Table wasobtained in the same manner as in Reference Example 17 using ethyl2-(piperidin-1-ylethyl)biphenyl-4-carboxylate as a starting material.

Reference Examples 45 to 56

The compound of Reference Example 45 shown in the following Table wasobtained in the same manner as in Reference Example 1.

The compound of Reference Example 46 shown in the following Table wasobtained in the same manner as in Reference Example 2.

The compounds of Reference Examples 47 to 50 shown in the followingTable were obtained in the same manner as in Reference Example 3.

The compounds of Reference Examples 51 to 56 shown in the followingTable was obtained in the same manner as in Reference Example 17.

Reference Example 57

To 160 ml of 1,2-dichloroethane was added 14.71 g of2-(hydroxymethyl)biphenyl-4-carboxylate, and thereto was added 0.5 ml ofDMF and 11.75 ml of thionyl chloride. After the reaction solution wasstirred for 1 hour under reflux with heating, 8 ml of thionyl chloridewas added at room temperature and the whole was stirred for 3 hoursunder reflux with heating. After cooling to room temperature, thereaction solvent was removed by evaporation under reduced pressure and200 ml of 1,2-dichloroethane was added to the residue. Under icecooling, 8.07 g of 1,3-benzothiazol-5-amine and 17.4 ml of pyridine wereadded thereto, followed by stirring at room temperature. The reactionsolvent was removed by evaporation under reduced pressure and theobtained residue was purified by silica gel column chromatography(hexane:ethyl acetate) to obtain 11.23 g of yellow foamyN-1,3-benzothiazol-5-yl-2-(chloromethyl)biphenyl-4-carboxamide.

Reference Example 58

In 50 ml of methylene chloride was dissolved 2.5 g of 6-nitroindoline,and then 6.37 ml of triethylamine was added thereto. Under ice cooling,3.51 g of methanesulfonyl chloride was added dropwise, the reactionsolution was stirred at room temperature for 3 hours, and then ice-waterwas added thereto, followed by 1 hour of stirring. The reaction solventwas removed by evaporation under reduced pressure, a 1M aqueoushydrochloric acid solution was added to the residue, and precipitatedwas filtrated off, whereby 3.52 g of 1-methylsulfonyl-6-nitroindolinewas obtained as a brown solid.

Reference Example 59

In 11.5 ml of DMF was dissolved 500 mg of6-nitro-2H-benzothiazin-3(4H)-one, and thereto was added 114 mg ofsodium hydride of 55% purity under ice cooling, followed by 30 minutesof stirring at room temperature. To the reaction solution was added 444μl of methyl iodide, and the whole was stirred at room temperature for 2hours. To the reaction solution was added 2 ml of methanol under icecooling, followed by 10 minutes of stirring at room temperature.Thereafter, water was added and the organic layer was extracted withethyl acetate. The organic layer was dried over anhydrous sodium sulfateand then the solvent was removed by evaporation. The obtained residuewas purified by silica gel column chromatography (chloroform) to obtain308 mg of 4-methyl-6-nitro-2H-1,4-benzothiazin-3(4H)-one.

Reference Examples 60 and 61

The compounds of Reference Examples 60 and 61 shown in the followingTable shown were obtained in the same manner as in Reference Example 59.

Reference Example 62

In 7.4 ml of tetrahydrofuran was dissolved 160 mg of2-chloro-5-nitro-1,3-benzothiazole, and thereto was added 1.86 ml of a1M dimethylamine tetrahydrofuran solution, followed by 16.5 hours ofstirring. Water was added to the reaction solution and the organic layerwas extracted with ethyl acetate. After the organic layer was dried overanhydrous sodium sulfate, the solvent was removed by evaporation. Theobtained residue was purified by silica gel column chromatography(hexane:ethyl acetate) to obtain 173 mg ofN,N-dimethyl-5-nitro-1,3-benzothiazol-2-amine as a yellow solid.

Reference Example 63

In 13.5 ml of a 2M dimethylamine tetrahydrofuran solution was dissolvedin 2.0 g of 2,3-dichloropyridine, followed by 6 hours of stirring at100° C. under sealed-tube conditions. After the reaction solution wascooled to room temperature, a saturated sodium bicarbonate solution wasadded thereto and an extraction operation was conducted with ethylacetate. The organic layer was dried over sodium sulfate, filtration wasconducted, and the filtrate was concentrated under reduced pressure toobtain 693 mg of a yellow oil. Then, 693 mg of the resulting oil wasdissolved in 5 ml of concentrated sulfuric acid, and a mixed solution of1.2 g of fuming nitric acid and 0.7 ml of concentrated sulfuric acid wasslowly added. After stirred for 30 minutes under ice cooling, cold waterwas added to the reaction solution and then sodium carbonate was addeduntil the solution was rendered basic. Ethyl acetate was added, theorganic layer was extracted, dried over sodium sulfate, and filtrated,and the filtrate was concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (hexane:ethylacetate) to obtain 347 mg of 3-chloro-N-methyl-5-nitropyridin-2-amine asa yellow solid.

Reference Example 64

In 20 ml of tert-butyl alcohol was dissolved 1.4 g of1-methyl-6-nitro-1H-indole, and then 3.5 g of N-bromosuccinimide wasadded as four divided portions.

After stirred at room temperature for 4 hours, the reaction solution wasconcentrated under reduced pressure. Water was added to the residue andthe organic layer was extracted with ethyl acetate. After the organiclayer was dried over anhydrous magnesium sulfate, the solvent wasremoved by evaporation. The obtained residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate) to obtain 2.44 g of3,3-dibromo-1-methyl-6-nitro-1,3-dihydro-2H-indol-2-one as a yellowsolid.

Reference Example 65

To 2.00 g of 1-methylsulfonyl-6-nitroindoline and a mixed solvent of 100ml of ethanol and 100 ml of tetrahydrofuran was added 300 mg of 10%palladium/carbon under an argon atmosphere, followed by 3 hours ofstirring at room temperature under a hydrogen atmosphere. The reactionsolution was filtrated through celite and the organic solvent in thefiltrate was removed under reduced pressure. To the residue was added200 ml of a mixed solution of methanol, ethyl acetate, andtetrahydrofuran. Under an argon atmosphere, 1 g of 10% palladium/carbonwas added and the whole was stirred at room temperature for 3 hoursunder a hydrogen atmosphere. The reaction solution was filtrated throughcelite and the organic solvent in the filtrate was removed under reducedpressure to obtain 1.66 g of 1-methylsulfonyl-6-aminoindoline as a paleyellow solid.

Reference Examples 66 to 71

The compounds of Reference Examples 66 to 71 shown in the followingTable were obtained in the same manner as in Reference Example 65.

Reference Example 72

In 70 ml of toluene was dissolved 3.2 g of ethyl4-formyl-3-nitrobenzoate and then 5.75 g of methyltriphenylphosphoranylideneacetate, followed by 6 hours of stirring underreflux. After cooling, the reaction solution was concentrated underreduced pressure and the obtained residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate) to obtain 3.63 g of ethyl4-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]-3-nitrobenzoate as a white solid.

Reference Example 73

To a mixture of 1.8 g of ethyl4-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]-3-nitrobenzoate, 32 ml of ethanoland 32 ml of tetrahydrofuran was added 640 mg of 10% palladium/carbonunder an argon atmosphere, followed by 2 hours of stirring at roomtemperature under a hydrogen atmosphere. The reaction solution wasfiltrated through celite and the organic solvent in the filtrate wasremoved under reduced pressure. To the residue were added 50 ml ofmethanol and 2 drops of concentrated hydrochloric acid, followed by 30minutes of stirring at 60° C. After cooling to room temperature, thereaction solution was concentrated under reduced pressure and water andchloroform were added to the residue, followed by an analyticaloperation. The organic layer was dried over anhydrous sodium sulfate andthe solvent was removed by evaporation. The obtained residue waspurified by silica gel column chromatography (hexane:ethyl acetate) toobtain 1.16 g of ethyl 2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylateas a white solid.

Reference Example 74

Into 10 ml of toluene was suspended 200 mg of1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylic acid, and then268 mg of diphenylphosphoryl azide (DPPA), 722 mg of tert-butyl alcohol,and 0.135 ml of triethylamine were added thereto, followed by 14 hoursof stirring under reflux with heating. After cooling, the reactionsolution was concentrated under reduced pressure, water was added to theresidue, and the organic layer was extracted with ethyl acetate. Afterthe organic layer was dried over anhydrous sodium sulfate, the solventwas removed by evaporation. To the residue was added 5 ml of a 4M ethylacetate solution of hydrochloric acid, followed by 7 hours of stirringat room temperature. Then, the reaction solution was concentrated underreduced pressure. To the residue was added a saturated aqueous sodiumhydrogen carbonate, and the organic layer was extracted with chloroform.After the organic layer was dried over anhydrous sodium sulfate, thesolvent was removed by evaporation. The obtained residue was purified bysilica gel column chromatography (chloroform:methanol:aqueous ammonia)to obtain 80 mg of 7-amino-1-methyl-3,4-dihydroquinolin-2(1H)-one as awhite solid.

Reference Example 75

A suspension of 329 mg of 3-chloro-N-methyl-5-nitropyridin-2-ylamine,489 mg of iron powder, and 9 ml of acetic acid was stirred at 60° C. for2 hours. After the reaction solution was cooled to room temperature,ethanol was added thereto and the solution was filtrated through celite.The filtrate was concentrated under reduced pressure and ethyl acetateand a saturated aqueous sodium bicarbonate solution were added thereto.To the organic layer obtained by an operation of separation was added a1M aqueous sodium hydroxide solution, followed by an operation ofseparation. The resulting organic layer was dried over anhydrous sodiumsulfate and filtrated and then the resulting filtrate was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (chloroform:methanol) to obtain 193 mg of3-chloro-2-methylamino-5-aminopyridine as a brown oil.

Reference Examples 76 to 124

The compound of Reference Example 76 shown in the following Table wasobtained in the same manner as in Reference Example 1.

The compound of Reference Example 77 shown in the following Table wasobtained in the same manner as in Reference Example 2.

The compounds of Reference Examples 78 to 80 shown in the followingTable were obtained in the same manner as in Reference Example 3.

The compounds of Reference Examples 81 to 83 shown in the followingTable were obtained in the same manner as in Reference Example 17.

The compounds of Reference Examples 84 to 89 shown in the followingTables were obtained in the same manner as in Reference Example 1.

The compounds of Reference Examples 90 to 95 shown in the followingTable were obtained in the same manner as in Reference Example 2.

The compounds of Reference Examples 96 to 124 shown in the followingTables were obtained in the same manner as in Reference Example 3.

Reference Example 125

2,4-Dinitrobenzaldehyde was dissolved in dioxane and water, methylacrylate and triethylenediamine were added thereto at room temperature,and the whole was stirred to obtain methyl 2-[(2,4-dinitrophenyl)(hydroxy)methyl]acrylate.

Reference Examples 126 to 162

The compounds of Reference Examples 126 to 162 shown in the followingTables were obtained in the same manner as in Reference Example 17.

Reference Example 163

N-(8-Chloro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-2,2,2-trifluoroacetamidewas hydrolyzed with sodium hydroxide to obtain6-amino-8-chloro-2H-1,4-benzoxazin-3(4H)-one.

Reference Examples 164 to 166

The compound of Reference Example 164 shown in the following Table wasobtained in the same manner as in Reference Example 41.

The compound of Reference Example 165 shown in the following Table wasobtained in the same manner as in Reference Example 42.

The compound of Reference Example 166 shown in the following Table wasobtained in the same manner as in Reference Example 43.

Reference Example 167

Ethyl 2-[(ethylamino)methyl]biphenyl-4-carboxylate andtetrahydro-4H-pyran-4-one were treated with sodium triacetoxyborohydridein the presence of acetic acid to obtain ethyl2-{[ethyl(tetrahydro-2H-pyran-4-yl)amino]methyl}biphenyl-4-carboxylate.

Reference Examples 168 to 189

The compounds of Reference Examples 168 to 170 shown in the followingTable were obtained using the same reagents as in Reference Example 167.

The compound of Reference Example 171 shown in the following Table wasobtained in the same manner as in Reference Example 57.

The compound of Reference Example 172 shown in the following Table wasobtained in the same manner as in Reference Example 58.

The compounds of Reference Examples 173 to 175 shown in the followingTables were obtained in the same manner as in Reference Example 59.

After N-alkylation was carried out in the same manner as in ReferenceExample 59, the compounds of Reference Examples 176 to 177 shown in thefollowing Table were obtained by hydrolyzing the ester group in the samemanner as in Reference Example 17.

The compounds of Reference Examples 178 to 179 shown in the followingTable were obtained in the same manner as in Reference Example 63.

Reference Example 180

Methyl 2,6-dichloro-5-fluoronicotinate was treated with dimethylamine ina sealed tube to obtain methyl2-chloro-6-(dimethylamino)-5-fluoronicotinate, which was then reactedunder a hydrogen atmosphere in the presence of palladium/carbon toobtain methyl 6-(dimethylamino)-5-fluoronicotinate.

Reference Examples 181 to 182

The compounds of Reference Examples 181 to 182 shown in the followingTables were obtained in the same manner as in Reference Example 65.

Reference Example 183

Ethyl (2S)-2-(2,4-dinitrophenoxy)propanoate was subjected to a reductionreaction with palladium/carbon under a hydrogen atmosphere in ethanol toobtain (2S)-6-amino-2-methyl-2H-1,4-benzoxadin-3(4H)-one.

Reference Examples 184 to 186

The compound of Reference Example 184 shown in the following Table wasobtained in the same manner as in Reference Example 183.

The compounds of Reference Examples 185 to 186 shown in the followingTable were obtained in the same manner as in Reference Example 72.

Reference Example 187

Palladium/carbon was added to an ethanol solution of[2,4-dinitro-6-(trifluoromethyl)phenyl]malonic acid dibenzyl ester andthe reaction was carried out under a hydrogen atmosphere to obtain6-amino-4-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one.

Reference Example 188

The compound of Reference Example 189 shown in the following Table wasobtained in the same manner as in Reference Example 188.

Reference Example 189

Methyl 3-amino-4-(1-hydroxy-3-methoxy-2-methyl-3-oxopropyl)benzoate wastreated with hydrochloric acid in 1,4-dioxane to obtain methyl3-methyl-2-oxo-1,2-dihydroquinolin-7-carboxylate.

Reference Example 190

Methyl 4-[(1E)-3-ethoxy-2-methyl-3-oxoprop-1-en-1-yl]-3-nitrobenzoateand palladium/carbon were added to ethanol and the whole was stirredunder a hydrogen atmosphere to obtain methyl3-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-carboxylate.

Reference Examples 191 to 198

The compounds of Reference Examples 191 to 198 shown in the followingTables were obtained in the same manner as in Reference Example 74.

Reference Example 199

Methyl 2-[(2,4-dinitrophenyl) (hydroxy)methyl]acrylate was reacted inethanol in the presence of palladium/carbon under a hydrogen atmosphereto obtain 7-amino-3-methyl-quinolin-2(1H)-one.

Reference Example 200

4-(t-Butoxycarbonyl)morpholine-2-carboxylic acid and diethylamine weredissolved in DMF, 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide wasadded thereto at room temperature, and the whole was stirred to obtaint-butyl 2-[(diethylamino)carbonyl]morpholine-4-carboxylate.

Reference Examples 201 to 203

The compounds of Reference Examples 201 to 203 shown in the followingTable were obtained in the same manner as in Reference Example 201.

Reference Example 204

N-(3-Aminophenyl)acetamide was treated with cinnamoyl chloride in thepresence of a base and then the resultingN-[3-(acetylamino)phenyl]-3-phenylacrylamide was treated with aluminumchloride to obtain N-(2-oxo-1,2-dihydroquinolin-7-yl)acetamide.

Reference Example 205

N-(3-Aminophenyl)acetamide was treated with 2-nitrophenylsulfonylchloride in the presence of triethylamine and then the resultingcompound was treated with iodomethane and potassium carbonate.Thereafter, the product was treated with thioglycolic acid to obtainN-[3-(methylamino)phenyl]acetamide.

Reference Example 206

The compound of Reference Example 206 shown in the following Table wasobtained in the same manner as in Reference Example 204.

Reference Example 207

A 1.2M hydrochloric acid-ethanol solution ofN-(2-oxo-1,2-dihydroquinolin-7-yl)acetamide was heated under reflux toobtain 7-aminoquinolin-2(1H)-one.

The compound of Reference Example 208 shown in the following Table wasobtained in the same manner as in Reference Example 207.

Reference Example 209

2-Chloro-1,5-dinitro-3-(trifluoromethyl)benzene was treated with malonicacid dibenzyl ester in the presence of sodium hydride to obtain[2,4-dinitro-6-(trifluoromethyl)phenyl]malonic acid dibenzyl ester.

Reference Example 210

The compound of Reference Example 210 shown in the following Table wasobtained in the same manner as in Reference Example 209.

Reference Example 211

Ethyl 5,6-dichloronicotinate, (2,4-dimethoxybenzyl)amine hydrochloride,and triethylamine were added to chloroform and the whole was stirred atroom temperature to obtain5-chloro-6-[(2,4-dimethoxybenzyl)amino]nicotinate.

Reference Example 212

5-Chloro-6-[(2,4-dimethoxybenzyl)amino]nicotinate was treated withsodium hydroxide in ethanol to obtain5-chloro-6-[(2,4-dimethoxybenzyl)amino]nicotinic acid. To the compoundwere added toluene, diphenylphosphoryl azide (DPPA), tert-butyl alcohol,and triethylamine, and the whole was stirred under reflux with heating.The resulting compound was treated with trifluoroacetic acid to obtain3-chloropyridin-2,5-diamine.

Reference Example 213

1-Methyl-5-nitro-1H-indol-2,3-dione was treated with(diethylamino)sulfur trifluoride to obtain3,3-difluoro-1-methyl-5-nitro-1,3-dihydro-2H-indol-2-one.

Reference Example 214

3,3-Difluoro-1-methyl-5-nitro-1,3-dihydro-2H-indol-2-one was subjectedto a hydrogenation reaction using a Raney-Ni catalyst under a hydrogenstream to obtain5-amino-3,3-difluoro-1-methyl-1,3-dihydro-2H-indol-2-one.

Reference Example 215

5-Nitro-3-(trifluoromethyl)pyridin-2(1H)-one was treated with thionylchloride and then the resulting2-chloro-5-nitro-3-(trifluoromethyl)pyridine was treated withdimethylamine to obtainN,N-dimethyl-5-nitro-3-(trifluoromethyl)pyridin-2-amine.

Reference Example 216

In the presence of potassium carbonate, 1-fluoro-2,4-dinitrobenzen wastreated with ethyl (2S)-(−)-2-hydroxypropanoate to obtain ethyl(2S)-2-(2,4-dinitrophenyl)propionate.

Reference Example 217

The compound of Reference Example 218 shown in the following Table wasobtained in the same manner as in Reference Example 217.

Reference Example 218

Trifluoroacetic anhydride was added to a mixed solution of6-amino-2H-1,4-benzoxazin-3(4H)-one and chloroform-tetrahydrofuran toobtain2,2,2-trifluoro-N-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)acetamide.

Reference Example 219

2,2,2-Trifluoro-N-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)acetamidewas treated with N-chlorosuccinimide in DMF to obtainN-(8-chloro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-2,2,2-trifluoroacetamide.

Reference Examples 220 to 221

The compounds of Reference Examples 220 to 221 shown in the followingTable were obtained in the same manner as in Reference Example 219.

Reference Example 222

Ethyl 3-chloro-4-hydroxy-5-methylbenzoate was treated withtrifluoromethanesulfonyl anhydride in the presence of a base to obtainethyl 3-chloro-5-methyl-4-{[(trifluoromethyl)sulfonyl]oxy}benzoate.

Reference Example 223

Ethyl2-({ethyl[(2-nitrophenyl)sulfonyl]amino}methyl)biphenyl-4-carboxylatewas treated with thioglycolic acid in the presence of a base to obtainethyl 2-[(ethylamino)methyl]biphenyl-4-carboxylate.

Reference Example 224

1-Chloro-2-methylpropan-2-ol was treated with ethylamine to obtain1-(ethylamino)-2-methylpropan-2-ol.

Reference Example 225

t-Butyl 2-[(diethylamino)carbonyl]morpholine-4-carboxylate was treatedwith a 4M ethyl acetate solution of hydrochloric acid in ethyl acetateto obtain N,N-diethylmorpholine-2-carboxamide hydrochloride.

Reference Examples 226 to 229

The compounds of Reference Examples 226 to 229 shown in the followingTable were obtained in the same manner as in Reference Example 225.

Reference Example 230

(2R,6S)-2,6-Dimethylpiperazine was treated with di-t-butylcarbonyl toobtain 4-butoxycarbonyl-2,6-dimethylpiperazine, which was then treatedwith acetyl chloride in dichloromethane in the presence of triethylamineto obtain 1-acetyl-4-butoxycarbonyl-2,6-dimethylpiperazine. Thereafter,the compound was treated with hydrochloric acid to obtain(2R,6S)-1-acetyl-2,6-dimethylpiperazine.

Reference Example 231

(2-Piperidin-1-ylethyl)amine was treated with 2-methylpropanoyl chloridein the presence of triethylamine to obtain2-methyl-N-(2-piperidin-1-ylethyl)propanamide.

Reference Example 232

The compound of Reference Example 232 shown in the following Table wasobtained in the same manner as in Reference Example 231.

Reference Example 233

(2R,6S)-1-Acetyl-2,6-dimethylpiperazine was reduced with lithiumaluminum hydride to obtain (2R,6S)-1-ethyl-2,6-dimethylpiperazine.

Reference Example 234

3-(Isobutylamino)propyl-2-methylpropanoate was reduced with lithiumaluminum hydride to obtain N-(3-hydroxypropyl)-2-methylpropanamide.

Reference Example 235

The compound of Reference Example 235 shown in the following Table wasobtained in the same manner as in Reference Example 234.

Example 1

Into 20 ml of 1,2-dichloroethane were suspended 500 mg of a mixture of2-(piperidin-1-ylmethyl)biphenyl-4-carboxylic acid and 1.5 equivalentsof sodium chloride, and then 174 mg of 3-methoxyaniline dissolved in 2ml of 1,2-dichloroethane was added thereto. Under ice cooling, 694 mg ofO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate and211 μl of N-methylmorpholine were added thereto, followed by 30 hours ofstirring at room temperature. Water was added to the reaction solutionand the organic layer was extracted with chloroform. The organic layerwas dried over anhydrous magnesium sulfate, followed by removal of thesolvent by evaporation. The obtained residue was purified by silica gelcolumn chromatography (chloroform:methanol:aqueous ammonia) to obtainN-(3-methoxyphenyl)-2-(piperidin-1-ylmethyl)biphenyl-4-carboxamide. Thecompound was dissolved in 3 ml of ethyl acetate and then 1 ml of a 4Methyl acetate solution of hydrochloric acid was added thereto. Thesolvent was removed by evaporation and crystallization was effected fromethanol to obtain 103 mg ofN-(3-methoxyphenyl)-2-(piperidin-1-ylmethyl)biphenyl-4-carboxamidehydrochloride as a white powder.

Example 2

A mixture of 227 mg of 3-aminophenol,3-(piperidin-1-ylmethyl)biphenyl-4-carboxylic acid (2.08 mmol), andsodium chloride was suspended into 7 ml of DMF and then 599 mg of1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide was added thereto at roomtemperature, followed by 10 hours of stirring. Ethyl acetate and a 1Maqueous hydrochloric acid solution were added to the reaction solutionand sodium hydrogen carbonate was added to the aqueous layer obtained byan operation of separation until the aqueous layer was rendered basic.Ethyl acetate was added to the aqueous layer and an operation ofseparation was conducted. The resulting organic layer was dried overanhydrous magnesium sulfate and then the solvent was removed byevaporation. The obtained white solid was dissolved in ethanol and a 4Methyl acetate solution of hydrochloric acid was added thereto, followedby removal of the solvent by evaporation. Ethanol and water were addedto the obtained reside and crystallization was effected to obtain 436 mgof N-(3-hydroxyphenyl)-3-(piperidin-1-ylmethyl)biphenyl-4-carboxamidehydrochloride as a white powder.

Example 3 to 9

The compounds of Examples 3 to 5 shown in the following Table wereobtained in the same manner as in Example 2.

The compounds of Examples 6 to 9 shown in the following Table wereobtained in the same manner as in Example 1.

Example 10

To 30 ml of thionyl chloride were added 500 mg of a mixture of2-(piperidin-1-ylmethyl)biphenyl-4-carboxylic acid and 1.5 equivalentsof sodium chloride and 1 drop of DMF under ice cooling, followed by 2hours of stirring at room temperature. The reaction solution wasconcentrated under reduced pressure and toluene was added to theresidue, followed by concentration under reduced pressure. After theresidue was dried under reduced pressure, 20 ml of methylene chloridewas added. Under ice cooling, 277 mg of 3,4,5-trichloroaniline and 0.59ml of triethylamine were added to the reaction mixture, and the wholewas stirred at room temperature for 3 hours and at 40° C. overnight. Thereaction mixture was concentrated under reduced pressure and the residuewas purified by silica gel column chromatography(chloroform:methanol:aqueous ammonia) to obtainN-(3,4,5-trichlorophenyl)-2-(piperidin-1-ylmethyl)biphenyl-4-carboxamide.The compound was dissolved in chloroform and 1 ml of a 4M dioxanesolution of hydrochloric acid was added thereto. The solvent was removedby evaporation and the resulting oil was crystallized from ether toobtain 450 mg ofN-(3,4,5-trichlorophenyl)-2-(piperidin-1-ylmethyl)biphenyl-4-carboxamidehydrochloride as a white powder.

Example 11 to 99

The compound of Example 11 shown in the following Table was obtained inthe same manner as in Example 10.

The compounds of Examples 12 to 43 shown in the following Tables wereobtained in the same manner as in Example 1.

The compounds of Examples 44 to 99 shown in the following Tables wereobtained in the same manner as in Example 10.

Example 100

To 10 ml of chloroform were added 250 mg ofN-1,3-benzothiazol-5-yl-2-(chloromethyl)biphenyl-4-carboxamide and 169mg of piperidine-4-carboxamide, followed by 3 days of stirring at roomtemperature. The reaction solvent was removed by evaporation underreduced pressure and the obtained residue was purified by silica gelcolumn chromatography (chloroform:methanol) to obtain a yellow foamysubstance. Thereto were added 2 ml of ethanol and 1 ml of a 4M ethylacetate solution of hydrochloric acid, followed by removal of thesolvent under reduced pressure. The residue was crystallized(ethanol:water:ethyl acetate) to obtain 205 mg of1-({4-[(1,3-benzothiazol-5-ylamino)carbonyl]biphenyl-2-yl}methyl)piperidine-4-carboxamidehydrochloride.

Example 101 to 111

The compounds of Examples 101 to 111 shown in the following Tables wereobtained in the same manner as in Example 100.

Example 112

In 5 ml of N,N-dimethylacetamide was dissolved 230 mg ofN-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)-2-(piperidin-1-ylmethyl)biphenyl-4-carboxamide,and then 252 mg of m-chloroperbenzoic acid was added under ice cooling,followed by 24 hours of stirring at room temperature. To the reactionsolution was added 5 ml of water and 1016 mg of sodium hydrogen sulfiteas two divided portions, followed by 2 hours of stirring at roomtemperature. Water was added to the reaction system, the organic layerwas extracted with ethyl acetate and dried over anhydrous sodiumsulfate, and the solvent was removed by evaporation. The obtainedresidue was purified by silica gel column chromatography(chloroform:methanol:aqueous ammonia) to obtain a yellow oil. It wasdissolved in 5 ml of ethyl acetate and then 1 ml of a 4M ethyl acetatesolution of hydrochloric acid was added thereto. The solvent was removedby evaporation and the resulting solid was recrystallized from ethanolto obtain 61 mg ofN-(4-methyl-1,1-dioxo-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)-2-(piperidin-1-ylmethyl)biphenyl-4-carboxamidehydrochloride as a white powder.

Example 113

The compounds of Example 113 shown in the following Table were obtainedin the same manner as in Example 10.

Example 114

Into 15 ml of methanol was suspended 250 mg ofN-(3-oxo-2,3-dihydro-1H-1-inden-5-yl)-2-(piperidin-1-ylmethyl)biphenyl-4-carboxamide,and then 40 mg of sodium borohydride was added at room temperature. Thereaction solution was stirred at room temperature for 1 hour and then 5ml of water was added. The reaction solution was subjected to removal byevaporation under reduced pressure. After the obtained residue wasdissolved in a mixed solution of chloroform and water, the solution wasextracted with chloroform. The organic layer was dried over anhydroussodium sulfate and then filtrated, and the solvent was removed byevaporation. The obtained residue was dissolved in 10 ml of ethanol andthen 0.5 ml of a 4M ethyl acetate solution of hydrochloric acid wasadded thereto. The solvent was removed by evaporation and the obtainedresidue was crystallized from ethanol to obtain 113 mg ofN-(3-hydroxy-2,3-dihydro-1H-1-inden-5-yl)-2-(piperidin-1-ylmethyl)biphenyl-4-carboxamidehydrochloride as a white powder.

Example 115 to 181

The compounds of Example 115 to 121 shown in the following Tables wereobtained in the same manner as in Example 1.

The compounds of Examples 122 and 123 shown in the following Table wereobtained in the same manner as in Example 2.

The compounds of Examples 124 to 181 shown in the following Tables wereobtained in the same manner as in Example 10.

Example 182

In 20 ml of DMF were dissolved 500 mg of4-{[(2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)amino]carbonyl}biphenyl-2-yl)methylmethanesulfonate, 123 mg of N-methylhexan-1-amine, 177 mg of potassiumcarbonate, and 212 mg of potassium iodide, followed by 3 hours ofstirring at 70° C. After subjected to an analytical operation, thesolvent was removed by evaporation. The obtained residue was purified bysilica gel column chromatography (chloroform:methanol:aqueous ammonia)to obtain a colorless viscous substance. Ethanol and 0.4 ml of a 4Methyl acetate solution of hydrochloric acid was added thereto and thesolvent was removed by evaporation. The residue was washed(2-propanol:ethanol) to obtain 233 mg of2-{[hexyl(methyl)amino]methyl}-N-(2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)biphenyl-4-carboxamide hydrochloride as a white solid.

Example 183 to 196

The compounds of Example 183 to 196 shown in the following Tables wereobtained in the same manner as in Example 182.

Example 197

To a 1,4-dioxane 0.7 ml solution of 19 mg ofN-1,3-benzothiazol-5-yl-2-(chloromethyl)biphenyl-4-carboxamide was addeda N-methyl-2-pyrrolidinone 0.1 ml solution of 12 mg of4-(4-chlorophenyl)pyrrolidine-3-methylcarboxylate, and further 14 mg ofpotassium carbonate and 12 mg of potassium iodide were added, followedby 1 day of stirring at room temperature. To the filtrate obtained byfiltrating the reaction solution was added 0.4 ml of ethyl acetate,extracted through a diatomaceous column containing 0.1 ml of water, andeluted with 0.4 ml of ethyl acetate. The solvent of the eluate wasremoved by evaporation under reduced pressure and the obtained residuewas purified preparatively by HPLC (column: Symmetry (registeredtrademark) C18 5 μm 19 mm×100 mm, solvent: MeOH/0.1% HCOOH—H₂O=10/90 (0min)-10/90 (1 min)-100/0 (9 min)-100/0 (12 min), flow rate: 30 mL/min)to obtain 0.4 mg ofmethyl-(3R,4S)-1-({4-[(1,4-benzothiazolo-5-ylamino)carbonyl]biphenyl-2-yl}methyl)-4-(4-chlorophenyl)pyrrolidine-3-carboxylate.

Examples 198 to 232

The compounds of Example 198 to 232 shown in the following Tables wereobtained in the same manner as in Example 197.

The structural formulae and physical properties of the above compoundsof Reference Examples and compounds of Examples are shown in thefollowing Tables 1 to 38. Moreover, the compounds described in thefollowing Tables 39 and 40 can be easily produced in about the samemanner as the methods described in the above Reference Examples,Examples, or production methods or by applying slightly changed methodsobvious for those skilled in the art to those methods. In thisconnection, the symbols in Tables have the following meanings.

Rf: Reference Example No., Ex: Example No., No: Compound No., Structure:structural formula, salt: salt (2HCl: dihydrochloride, no descriptionshows a free base), Me: methyl group, Et: ethyl group, Ac: acetyl group,iPr: isopropyl group, nPr: n-propyl group, tBu: t-butyl group, Boc:t-butoxycarbonyl group, Ph: phenyl group, Ts: p-toluenesulfonyl group,Ms: methanesulfonyl group, DATA: physical property data, NMR: nuclearmagnetic resonance spectrum (TMS internal standard: ¹H NMR: 400 MHz or300 MHz, solvent in case that particularly not specified: DMSO-d₆), FP:FAB-MS (M+H)⁺, H: retention time on HPLC under the following HPLCconditions (minute), Conditions

Column: Wakosil-II 5C18 AR 2 mm×30 mm, solvent: MeOH/5 mMtrifluoroacetic acid-H₂O=10/90 (0 min)-100/0 (4.0 min)-100/0 (4.5 min),flow rate: 1.2 mL/min.

INDUSTRIAL APPLICABILITY

Since the compounds of the present invention have an excellentinhibitory activity of capsaicin receptor VR1 activation, they areuseful as medicaments, particularly therapeutic agents for various painsincluding neuropathic pains and inflammatory pains, headaches such asmigraine and cluster headache, pruritus, bladder diseases includingoveractive bladder and interstitial cystitis, and the like.

The excellent inhibitory activity on capsaicin receptor VR1 activationof the compounds of the invention is confirmed by test methods shownbelow.

Test Example 1 Receptor Binding Assay Using VR1 Stably Expressing Cell

1) Construction of Human VR1 Stably Expressing Cell

A full-length cDNA encoding human VR1 was obtained by the followingmethod. First, human brain mRNA was reverse transcribed using a reversetranscriptase to synthesize a first strand cDNA. Then, using the firststrand cDNA as a template, PCR according to Hot Start method was carriedout using Taq DNA polymerase. The above PCR was carried out by firstconducting thermal denaturation of 98° C. (1 min) and then repeating acycle consisting of 98° C. (15 sec)/63° C. (30 sec)/72° C. (3 min) 35times using an oligonucleotide consisting of a base sequence of 424th to443rd in a known human VR1 cDNA sequence (Genbank AJ277028.1) as a senseprimer and an oligonucleotide consisting of a complimentary sequence ofa base sequence of 3082nd to 3100th as an antisense primer.

An amplified DNA fraction was cloned using pCR-XL-TOPO vector (TOPO XLPCR Cloning Kit; Invitrogen, USA). The resulting plasmid DNA wasdigested with a restriction enzyme EcoRI to isolate human VR1-cDNAalone, which was then integrated into pcDNA3.1(+) plasmid (Invitrogen,USA). The above genetic engineering operations were carried out inaccordance with known methods (Sambrook, J. et al, Molecular Cloning—ALaboratory Manual”, Cold Spring Harbor Laboratory Press, NY, 2001) anddirections attached to individual reagents.

Next, the resulting pcDNA3.1-VR1 was transduced into HEK293 cells orCHO-KL cells. VR1/HEK293 cells were selected using a DMEM medium(Invitrogen, USA) containing 10% FBS, 100 μg/ml streptomycin, 100 U/mlpenicillin, and 400 μg/ml G418 and VR1/CHO cells were selected using aHumF12 medium (Invitrogen, USA) containing 10% FBS, 100 μg/mlstreptomycin, 100 U/ml penicillin, and 400 μg/ml G418 to preparereceptor stably expressing cell lines. The receptor stably expressingcells were subcultured in respective above media.

2) A Method of Membrane Preparation

After the above VR1/HEK293 cells were cultured in glass dishes in alarge quantity, the medium was removed and cells were scraped up withadding ice-cooled PBS. They were centrifuged at 1,000 rpm at 4° C. for10 minutes. After a buffer for homogenization (25 mM Tris-HCl, 220 mMsucrose, pH 7.4) was added to the resulting sediment and the whole washomogenized, it was centrifuged at 2,200 rpm at 4° C. for 10 minutes.The resulting supernatant was centrifuged at 30,000×g at 4° C. for 20minutes and an operation of adding 25 mM Tris-HCl, pH 7.4 to theresulting sediment and centrifuging it at 30,000×g at 4° C. for 20minutes was repeated twice. The resulting sediment was suspended in 25mM Tris-HCl, pH 7.4 and protein concentration was determined using aprotein assay staining solution (Bio Rad, USA). The membrane preparationthus prepared was stored at −80° C.

3) Receptor Binding Assay

The test was carried out by modifying the method of [Neurosci. 57:747-757 (1993)]. Assay buffer (25 mM Tris-HCl, 0.025% BSA, pH 7.4) (147μl), 3 μl of a test compound, 50 μl of [³H]RTX (about 50,000 dpm;Perkin-Elmer Life Science, USA), 100 μl of the above membranepreparation (protein amount of about 25 μg) were mixed and incubated at37° C. for 60 minutes, and then the whole was incubated on ice for 10minutes. An ice-cooled α₁ acid protein (AGP; Sigma) was added in anamount of 200 μg/50 μl, followed by further 5 minutes of incubation. Thecompletion of the incubation was effected by rapid filtration of themixture using a GF/B filter (Perkin-Elmer Life Science, USA). After thefilter was washed with ice-cooled 25 mM Tris-HCl buffer (pH 7.4) seventimes, radioactivity of the filter was measured by means of a liquidscintillation counter (2500TR; Packard, USA). With regard to a specificbinding, of the total binding amount of [³H]RTX and membrane fractionsof VR1 receptor stably expressing cell, a portion substituted by 1 μMRTX was regarded as a specific binding derived from VR1 receptor.Evaluation of the test compound was conducted as follows. Namely, abinding decrease at the addition of the compound was determined as arelative value when a binding decrease at the addition of RTX wasregarded as 100%. Then, an IC₅₀ value was calculated according to thelogistic regression method.

For example, the compounds of Examples 1, 7, 21, 33, 60, 71, 78, 85, 87,110, 117, 122, 123, 129, 130, 143, 163, 170, 181, and 195 showed an IC₅₀value of 1 μM or less. By the present test, it was confirmed that thecompounds of the invention had affinity to VR1 receptor.

Test Example 2 ⁴⁵Ca Uptake Assay Using VR1 Stably Expressing Cell

VR1/CHO cells were seeded in a 96-well white culture plate in a densityof 30,000 cells per well. After 24 hours of culture in theprevious-mentioned medium, the medium was replaced by 25 μl of assaybuffer (PBS, 0.1 mM CaCl₂, 1 mM MgCl₂, 10 mM HEPES, 10 mM glucose,0.025% BSA, pH 7.4), followed by 10 minutes of incubation at 37° C. Tothe well was added 25 μl of a mixed solution of about 4 kBq of ⁴⁵Ca,capsaicin (Sigma, USA) adjusted so as to be a final concentration of 300nM, and a test compound, followed by 10 minutes of incubation at 37° C.The mixed solution was washed with a buffer for washing (PBS, 0.1 mMCaCl₂, 1 mM MgCl₂) three times, 17 μl of 0.1N NaOH and 100 μl of aliquid scintillator (microscinti-PS; Perkin-Elmer Life Science, USA)were added, and radioactivity was measured by means of a scintillationcounter for microplate (Top Count; Perkin-Elmer Life Science, USA). VR1receptor-specific ⁴⁵Ca uptake induced by capsaicin was determined as adecrease induced by 10 μM capsazepine, VR1 antagonist, (Sigma, USA) fromtotal ⁴⁵Ca uptake in the cell at the stimulation with 300 nM capsaicin.Evaluation of the test compound was conducted as follows. Namely, anuptake decrease at the addition of the compound was determined as arelative value when an uptake decrease at the addition of capsazepinewas regarded as 100%. Then, an IC₅₀ value was calculated according tothe logistic regression method.

As a result, the compounds of the invention showed a potent inhibitoryactivity against ⁴⁵Ca uptake via VR1.

Test Example 3 Capsaicin Test

The test was carried out in accordance with [Neuropharmacol. 31:1279-1285 (1992)]. When 1.6 μg of capsaicin was administered to theplanta of a mouse (ddY, male, 4- to 5-weeks old), a paw-licking actionis induced. By measuring a time of expressing paw-licking action during5 minutes after the administration, an inhibitory effect on painbehavior was evaluated. A test compound was administeredintraperitoneally 30 minutes before the capsaicin administration oradministered orally 45 minutes before the capsaicin administration.Evaluation of the test compound was conducted by determining eachinhibition ratio in a test compound-administered group when the time ofexpressing paw-licking action in a vehicle-administered group wasregarded as 100%.

As a result, the compounds of the invention showed a potent inhibitoryeffect on pain behavior in both of intraperitoneal administration andoral administration. With regard to representative compounds ofExamples, inhibition ratios in the orally administered group (30 mg/kg)are shown in the following Table 41.

TABLE 41 Inhibition Compound ratio (%) Example 33 66 Example 78 76Example 85 86 Example 87 67 Reference 17 (26²⁾) compound¹⁾ Example 12369 Example 129 91 Example 130 62 Example 170 68 ¹⁾The compound ofexample 115 in Patent Document 3 ²⁾A value at oral administration of 100mg/kg

On the other hand, the compound of example 115 described in the abovePatent Document 3 did not show a significant inhibitory activity even ata dose of 100 mg/kg in the present test.

As a result of Test Examples 1 to 3, since the compounds of theinvention show a remarkable pain inhibitory activity based on inhibitionof VR1 receptor activation, it is expected that they can be effectiveanti-analgesics.

A pharmaceutical composition containing one or more types of thecompounds of the invention and pharmaceutically acceptable salts thereofas the active ingredient can be prepared into tablets, powders, finegranules, granules, capsules, pills, liquids, injections, suppositories,ointments, paps, and the like, using carriers and excipients generallyused for formulation, and other additives, which are orally orparenterally administered.

As the solid composition for oral administration in accordance with theinvention, tablets, powders, granules, and the like are used. For such asolid composition, one or more active substances are mixed with at leastone inactive diluent, for example lactose, mannitol, glucose,hydroxypropyl cellulose, microcrystalline cellulose, starch,polyvinylpyrrolidone, magnesium metasilicate aluminate, and the like.According to usual methods, the composition may contain additives otherthan inactive diluents, for example lubricants such as magnesiumstearate, disintegrators such as cellulose calcium glycolate,stabilizers, solubilizers, or dissolution-auxiliary agents. Ifnecessary, the tablets or pills may be coated with coating agentsdissolvable in stomach or intestine.

The liquid composition for oral administration includes pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirs, andthe like and contains inactive diluents generally used, for examplepurified water and ethyl alcohol. The composition may contain auxiliaryagents such as solubilizers, dissolution-auxiliary agents, moisturizersand suspending agents, sweeteners, flavoring agents, aromatic agents,and preservatives.

The injections for parenteral administration encompass aseptic, aqueousor non-aqueous solutions, suspensions, and emulsions. The diluents foraqueous solutions and suspensions include, for example, distilled waterfor injections and physiological saline. The diluents for non-aqueoussolutions and suspensions include, for example, propylene glycol,polyethylene glycol, vegetable oils such as olive oil, alcohols such asethyl alcohol, polysorbate 80 (trade name), and the like.

Such composition may further contain additives including isotonicagents, preservatives, moisturizers, emulsifiers, dispersants,stabilizers, solubilizers, and dissolution-auxiliary agents. These maybe sterilized by filtration through, for example, bacteria-retainingfilter, blending with germicides, or irradiation. These may be alsoprepared into aseptic solid compositions and the compositions may beused, after dissolution in aseptic water or aseptic solvents forinjections prior to use.

The clinical dose of the compounds of the invention to humans isappropriately determined in consideration of symptom, body weight, age,sex, and the like of patients to be applied. However, the dose isusually from 0.1 to 500 mg per day per adult in the case of oraladministration and from 0.01 to 100 mg in the case of parenteraladministration, which is administered once a day or by dividing intoseveral doses. Since the dose may vary depending on various conditions,it is sufficient in a smaller amount than the above dose range in somecases.

TABLE 1 Rf Structure(salt) DATA 1

FAB-MS 241 (M + H)⁺ 2

FAB-MS 319 (M + H)⁺ 3

FAB-MS 324 (M + H)⁺ 4

FAB-MS 310 (M + H)⁺ 5

FAB-MS 310 (M + H)⁺ 6

FAB-MS 367 (M + H)⁺ 7

FAB-MS 338 (M + H)⁺ 8

FAB-MS 326 (M + H)⁺ 9

FAB-MS 339 (M + H)⁺ 10

FAB-MS 402 (M + H)⁺ 11

FAB-MS 322 (M + H)⁺ 12

FAB-MS 372 (M + H)⁺ 13

FAB-MS 312 (M + H)⁺ 14

FAB-MS 374 (M + H)⁺ 15

FAB-MS 342 (M + H)⁺ 16

FAB-MS 372 (M + H)⁺ 17

FAB-MS 296 (M + H)⁺ 18

FAB-MS 310 (M + H)⁺ 19

FAB-MS 282 (M + H)⁺ 20

FAB-MS 339 (M + H)⁺ 21

FAB-MS 310 (M + H)⁺ 22

FAB-MS 298 (M + H)⁺

TABLE 2 Rf Structure(salt) DATA 23

FAB-MS 311 (M + H)⁺ 24

FAB-MS 374 (M + H)⁺ 25

FAB-MS 294 (M + H)⁺ 26

FAB-MS 344 (M + H)⁺ 27

FAB-MS 284 (M + H)⁺ 28

FAB-MS 346 (M + H)⁺ 29

FAB-MS 314 (M + H)⁺ 30

FAB-MS 344 (M + H)⁺ 31

FAB-MS 338 (M + H)⁺ 32

FAB-MS 338 (M + H)⁺ 33

FAB-MS 352 (M + H)⁺ 34

FAB-MS 352 (M + H)⁺ 35

FAB-MS 380 (M + H)⁺ 36

FAB-MS 310 (M + H)⁺ 37

FAB-MS 310 (M + H)⁺ 38

FAB-MS 324 (M + H)⁺ 39

FAB-MS 324 (M + H)⁺ 40

FAB-MS 352 (M + H)⁺ 41

FAB-MS 254 M⁻ 42

FAB-MS 269 (M + H)⁺ 43

FAB-MS 338 (M + H)⁺ 44

FAB-MS 310 (M + H)⁺

TABLE 3 Rf Structure(salt) DATA 45

FAB-MS 259 (M + H)⁺ 46

FAB-MS 337 (M + H)⁺ 47

FAB-MS 416 (M + H)⁺ 48

FAB-MS 342 (M + H)⁺ 49

FAB-MS 342 (M + H)⁺ 50

FAB-MS 360 (M + H)⁺ 51

FAB-MS 388 (M + H)⁺ 52

FAB-MS 314 (M + H)⁺ 53

FAB-MS 314 (M + H)⁺ 54

FAB-MS 332 (M + H)⁺ 55

FAB-MS 227 (M + H)⁻ 56

FAB-MS 206 (M + H)⁺ 57

FAB-MS 379 (M + H)⁺ 58

FAB-MS 242 M⁺ 59

FAB-MS 224 M⁻ 60

FAB-MS 211 (M + H)⁺ 61

FAB-MS 234 (M + H)⁺ 62

ESI-MS 224 (M + H)⁺ 63

FAB-MS 188 (M + H)⁺ 64

EI-MS 350 M⁺

TABLE 4 Rf Structure(salt) DATA 65

FAB-MS 213 (M + H)⁺ 66

FAB-MS 193 (M + H)⁺ 67

EI-MS 166 M⁺ 68

EI-MS 193 M⁺ 69

EI-MS 162 M⁺ 70

FAB-MS 177 (M + H)⁺ 71

FAB-MS 185 (M + H)⁺ 72

FAB-MS 280 (M + H)⁺ 73

FAB-MS 220 (M + H)⁺ 74

ESI-MS 177 (M + H)⁺ 75

FAB-MS 158 (M + H)⁺ 76

FAB-MS 241 (M + H)⁺ 77

EI-MS 318, 320 M⁺ 78

FAB-MS 284 (M + H)⁺ 79

FAB-MS 324 (M + H)⁺ 80

FAB-MS 284 (M + H)⁺ 81

FAB-MS 296 (M + H)⁺ 82

FAB-MS 254 (M − H)⁻ 83

FAB-MS 256 (M + H)⁺ 84

FAB-MS 275 (M + H)⁺ 85

FAB-MS 275 (M + H)⁺ 86

FAB-MS 309 (M + H)⁺

TABLE 5 Rf Structure(salt) DATA 87

FAB-MS 247 (M + H)⁺ 88

FAB-MS 275 (M + H)⁺ 89

FAB-MS 275 (M + H)⁺ 90

NMR δ 1.32-1.40 (3 H, m), 4.30-4.40 (2 H, m), 4.68 (2 H, brs), 7.38-8.20 (7 H, m) 91

NMR δ 1.30-1.40 (3 H, m), 4.30- 4.44 (2 H, m), 4.67 (2 H, brs),7.40-8.25 (7 H, m) 92

NMR δ 1.30-1.40 (3 H, m), 4.30- 4.44 (2 H, m), 4.66 (2 H, brs),7.46-8.25 (7 H, m) 93

NMR δ 1.29-1.40 (3 H, m), 4.29- 4.44 (2 H, m), 4.87 (2 H, brs),7.23-8.24 (6 H, m) 94

FAB-MS 353 (M + H)⁺ 355 (M + H)⁺ 95

GC-MS 336 M⁺ 338 M⁺ 96

FAB-MS 358 (M + H)⁺ 97

FAB-MS 358 (M + H)⁺ 98

FAB-MS 392 (M + H)⁺ 99

FAB-MS 330 (M + H)⁺ 100

FAB-MS 349 (M + H)⁺ 101

FAB-MS 368 (M + H)⁺ 102

FAB-MS 435 (M + H)⁺ 103

FAB-MS 338 (M + H)⁺ 104

FAB-MS 354 (M + H)⁺ 105

FAB-MS 423 (M + H)⁺ 106

FAB-MS 423 (M + H)⁺ 107

FAB-MS 324 (M + H)⁺ 108

FAB-MS 354 (M + H)⁺

TABLE 6 Rf Structure(salt) DATA 109

FAB-MS 354 (M + H)⁺ 110

FAB-MS 324 (M + H)⁺ 111

FAB-MS 392 (M + H)⁺ 112

FAB-MS 409 (M + H)⁺ 113

FAB-MS 469 (M + H)⁺ 114

FAB-MS 409 (M + H)⁺ 115

FAB-MS 407 (M + H)⁺ 116

FAB-MS 425 (M + H)⁺ 117

FAB-MS 425 (M + H)⁺ 118

FAB-MS 342 (M + H)⁺ 119

FAB-MS 358 (M + H)⁺ 120

FAB-MS 338 (M + H)⁺ 121

FAB-MS 356 (M + H)⁺ 122

FAB-MS 407 (M + H)⁺ 123

FAB-MS 421 (M + H)⁺ 124

FAB-MS 397 (M + H)⁺ 125

FAB-MS 282 M⁻ 126

FAB-MS 218 (M + H)⁺ 127

FAB-MS 234 (M + H)⁺ 128

FAB-MS 220 (M + H)⁺ 129

ESI-MS 245, 247 (M + H)⁺ 130

ESI-MS 201 (M + H)⁺

TABLE 7 Rf Structure(salt) DATA 131

ESI-MS 185 (M + H)⁺ 132

FAB-MS 310 (M + H)⁺ 133

FAB-MS 330 (M + H)⁺ 134

FAB-MS 330 (M + H)⁺ 135

FAB-MS 364 (M + H)⁺ 136

FAB-MS 302 (M + H)⁺ 137

FAB-MS 321 (M + H)⁺ 138

FAB-MS 340 (M + H)⁺ 139

FAB-MS 356 (M + 2H)⁺ 140

FAB-MS 369 (M + H)⁺ 141

FAB-MS 340 (M + H)⁺ 142

FAB-MS 407 (M + H)⁺ 143

FAB-MS 310 (M + H)⁺ 144

FAB-MS 326 (M + H)⁺ 145

FAB-MS 395 (M + H)⁺ 146

FAB-MS 395 (M + H)⁺ 147

FAB-MS 296 (M + H)⁺ 148

FAB-MS 326 (M + H)⁺ 149

FAB-MS 326 (M + H)⁺ 150

FAB-MS 296 (M + H)⁺ 151

FAB-MS 364 (M + H)⁺ 152

FAB-MS 381 (M + H)⁺

TABLE 8 Rf Structure(salt) DATA 153

FAB-MS 381 (M + H)⁺ 154

FAB-MS 379 (M + H)⁺ 155

FAB-MS 397 (M + H)⁺ 156

FAB-MS 397 (M + H)⁺ 157

FAB-MS 314 (M + H)⁺ 158

FAB-MS 330 (M + H)⁺ 159

FAB-MS 310 (M + H)⁺ 160

FAB-MS 328 (M + H)⁺ 161

FAB-MS 379 (M + H)⁺ 162

FAB-MS 393 (M + H)⁺ 163

FAB-MS 198 M⁺ 164

FAB-MS 254 M⁺ 165

FAB-MS 269 (M + H)⁺ 166

FAB-MS 338 (M + H)⁺ 167

FAB-MS 368 (M + H)⁺ 168

FAB-MS 384 (M + H)⁺ 169

FAB-MS 269 (M + H)⁺ 170

FAB-MS 283 (M + H)⁺ 171

ESI-MS 405 (M + H)⁺ 172

FAB-MS 467 (M + H)⁺ 173

FAB-MS 232 (M + H)⁺ 174

FAB-MS 262 (M + H)⁺

TABLE 9 Rf Structure(salt) DATA 175

FAB-MS 234 (M + H)⁺ 176

ESI-MS 220 (M + H)⁺ 177

ESI-MS 238 (M + H)⁺ 178

ESI-MS 230 (M + H)⁺ 179

ESI-MS 259, 261 (M + H)⁺ 180

ESI-MS 199 (M + H)⁺ 181

ESI-MS 206 (M + H)⁺ 182

FAB-MS 177 (M + H)⁺ 183

FAB-MS 179 (M + H)⁺ 184

FAB-MS 179 (M + H)⁺ 185

ESI-MS 281 (M + H)⁺ 186

FAB-MS 294 (M + H)⁺ 187

ESI-MS 217 (M + H)⁺ 188

FAB-MS 162 (M + H)⁺ 189

FAB-MS 218 (M + H)⁺ 190

FAB-MS 220 (M + H)⁺ 191

ESI-MS 191 (M + H)⁺ 192

ESI-MS 209 (M + H)⁺ 193

FAB-MS 189 (M + H)⁺ 194

FAB-MS 205 (M + H)⁺ 195

ESI-MS 156 (M + H)⁺ 196

ESI-MS 172 (M + H)⁺

TABLE 10 Rf Structure(salt) DATA 197

ESI-MS 216, 218 (M + H)⁺ 198

EI-MS 190 M⁺ 199

FAB-MS 175 (M + H)⁺ 200

FAB-MS 287 (M + H)⁺ 201

FAB-MS 287 (M + H)⁺ 202

FAB-MS 271 (M + H)⁺ 203

FAB-MS 389 (M + H)⁺ 204

FAB-MS 203 (M + H)⁺ 205

FAB-MS 165 (M + H)⁺ 206

EI-MS 216 M⁺ 207

EI-MS 160 M⁺ 208

EI-MS 174 M⁺ 209

ESI-MS 517 (M + H)⁺ 210

FAB-MS 465 (M + H)⁺ 211

ESI-MS 351 (M + H)⁺ 212

ESI-MS 144 (M + H)⁺ 213

FAB-MS 229 (M + H)⁺ 214

EI-MS 198 M⁺ 215

FAB-MS 236 (M + H)⁺ 216

FAB-MS 285 (M + H)⁺ 217

FAB-MS 271 (M + H)⁺ 218

FAB-MS 261 (M + H)⁺

TABLE 11 Rf Structure(salt) DATA 219

FAB-MS 293 (M − H)⁻ 220

EI-MS 196 M⁺ 221

FAB-MS 215 (M + H)⁺ 222

NMR (300 MHz, DMSO-d₆) δ 1.33 (3 H, t, J = 5.1 Hz), 2.47 (3 H, s), 4.35(2 H, q, J = 5.1 Hz), 8.03 (1 H, s), 8.04 (1 H, s) 223

FAB-MS 284 (M + H)⁺ 224

FAB-MS 118 (M + H)⁺ 225

FAB-MS 187 (M + H)⁺ 226

FAB-MS 187 (M + H)⁺ 227

FAB-MS 171 (M + H)⁺ 228

FAB-MS 169 (M + H)⁺ 229

EI-MS 182 M⁺ 230

GC-MS 156 M⁺ 231

FAB-MS 199 (M + H)⁺ 232

FAB-MS 216 (M + H)⁺ 233

GC-MS 142 M⁺ 234

FAB-MS 132 (M + H)⁺ 235

LC-MS 185 (M + H)⁺

TABLE 12 Ex Structure(salt) DATA 1

NMR: δ1.20-1.35(1H, m), 1.53-1.63(3H, m), 1.75-1.91(2 H m),2.54-2.65(2H, m), 3.16-3.25(2H, m), 3.76(3H, s), 4.37(2H, d, J = 5.1Hz),6.70(1H, dd, J = 8.3, 2.0Hz), 7.26(1 H t, J = 8.2Hz), 7.37-7.43(2H, m),7.45-7.58(5H, m), 7.63- 7.67(1H, m), 8.02(1H, d, J = 7.8Hz),8.70-8.75(1H, m), 10.22 (1H, brs), 10.58(1H, s). FAB-MS: 401(M + H)⁺ 2

NMR: δ1.35-1.49(1H, m), 1.64-1.72(1H, m), 1.75-1.85(4 H m),2.93-3.06(2H, m), 3.36-3.42(2H, m), 4.47(2H, d, J = 5.2Hz),6.53-6.59(1H, m), 7.11-7.17(2H, m), 7.34(1H, s), 7.43-7.48(1H, m),7.51-7.57(2H, m), 7.83-8.89(3H, m), 7.91-7.95(1H, m), 8.25(1H, s),9.52(1H, s), 10.04(1 H brs), 10.56(1H, s). FAB-MS: 387(M + H)⁺ 3

NMR: 2.79(3H, s), 2.80(3H, s), 4.43(2H, d, J = 5.4Hz), 6.54- 6.60(1H,m), 7.11-7.21(2H, m), 7.33(1H, s), 7.43-7.48 (1H, m), 7.51-7.56(2H, m),7.84-7.96(4H, m), 8.20(1H, d, J = 1.5Hz), 9.56(1H, s), 10.18(1H, brs),10.60(1H, s). FAB-MS: 347(M + H)⁺ 4

NMR: δ1.19-1.34(1H, m), 1.52-1.63(3H, m), 1.73-1.88(2 H m),2.53-2.64(2H, m), 3.18-3.24(2H, m), 4.37(2H, d, J = 5.4Hz),6.50-6.55(1H, m), 7.13(1H, t, J = 8.21Hz), 7.29-7.33 (1H, m),7.37-7.42(2H, m), 7.44-7.56(5H, m), 8.02(1H, dd, J = 8.1, 1.7Hz),8.67(1H, d, J = 1.7Hz), 9.45(1H, s), 10.19 (1H, brs), 10.44(1H, s).FAB-MS: 387(M + H)⁺ 5

NMR: δ2.55(6H, s), 4.38(2H, s), 6.49-6.56(1H, m), 7.13 (1H, t, J =8.3Hz), 7.28(1H, d, J = 8.3Hz), 7.39(2H, d, J = 7.8 Hz), 7.43-7.57(5H,m), 8.03(1H, d, J = 8.3Hz), 8.54(1H, s), 9.54(1H, s), 10.32(1H, s),10.36(1H, brs). FAB-MS: 347 (M + H)⁺ 6

NMR: δ1.26-1.42(1H, m), 1.61-1.79(5H, m), 2.72-2.85(2 H m),3.04-3.13(2H, m), 3.22-3.36(4H, m), 7.39-7.45(3 H m), 7.45-7.50(1H, m),7.45-7.56(2H, m), 7.90-8.01(2 H m), 8.10-8.16(2H, m), 8.70(1H, d, J =1.9Hz), 9.40(1H, s), 9.97(1H, brs), 10.69(1H, s). FAB-MS: 442(M + H)⁺ 7

NMR: δ1.20-1.33(1H, m), 1.52-1.65(3H, m), 1.74-1.93(2 H m),2.54-2.68(2H, m), 3.18-3.28(2H, m), 4.41(2H, d, J = 5.4Hz), 7.42(2H, d,J = 6.8Hz), 7.46-7.58(4H, m), 8.02- 8.10(2H, m), 8.15(1H, d, J = 8.8Hz),8.79(2H, s), 9.42(1H, s), 10.20(1H, brs), 10.88(1H, brs). FAB-MS:428(M + H)⁺ 8

NMR: δ1.20-1.34(1H, m), 1.52-1.66(3H, m), 1.81-1.97(2 H m),2.55-2.68(2H, m), 2.81(3H, m), 3.17-3.30(2H, m), 4.39(2H, d, J = 4.8Hz),7.41(2H, d, J = 7.4Hz), 7.46-7.58(4 H m), 8.01(2H, s), 8.04(1H, d, J =7.8Hz), 8.63(1H, s), 8.85 (1H, s), 10.39(1H, brs), 10.87(1H, s). FAB-MS:442(M + H)⁺ 9

NMR: δ1.20-1.35(1H, m), 1.52-1.62(3H, m), 1.78-1.92(2 H m),2.53-2.64(2H, m), 2.90(6H, s), 3.17-3.26(2H, m), 4.37 (2H, d, J =5.4Hz), 6.50(1H, dd, J = 8.3, 1.9Hz), 7.15(1H, t, J = 8.3Hz),7.33-7.43(4H, m), 7.45-7.56(4H, m), 8.01(1 H dd, J = 8.3, 2.0Hz),8.74-8.76(1H, m), 10.34(1H, brs), 10.40 (1H, s). FAB-MS: 414(M + H)⁺

TABLE 13 Ex Structure(salt) DATA 10

NMR: δ1.20-1.38(1H, m), 1.52-1.68(3H, m), 1.78-1.96 (2H, m),2.55-2.70(2H, m), 3.18-3.28(2H, m), 4.38(2 H d, J = 4.4Hz), 7.39(2H, d,J = 7.4Hz), 7.45-7.60(5H, m), 8.02(1H, d, J = 7.8Hz), 8.33(2H, s),8.78(1H, s), 10.07 (1H, s). FAB-MS: 473(M + H)⁺ 11

NMR: δ1.20-1.33(1H, m), 1.53-1.63(3H, m), 1.75-1.90 (2H, m), 2.35(3H,s), 2.52-2.66(2H, m), 3.15-3.25(2 H m), 4.37(2H, d, J = 6.6Hz),7.37-7.42(2H, m), 7.46-7.58 (5H, m), 7.76(1H, dd, J = 8.8, 2.5Hz),7.97(1H, d, J = 2.5 Hz), 8.01(1H, dd, J = 8.3, 1.9Hz), 8.72(1H, d, J =1.9Hz), 10.17(1H, s), 10.69(1H, s). FAB-MS: 463(M + H)⁺ 12

NMR: δ1.20-1.35(1H, m), 1.53-1.63(3H, m), 1.70-.185 (2H, m),2.53-2.65(2H, m), 3.16-3.24(2H,, m), 4.37(2 H d, J = 5.3Hz), 4.55(2H,s), 6.94(1H, d, J = 8.8Hz), 7.35 (1H, dd, J = 8.6, 2.3Hz), 7.38-7.42(2H,m), 7.46-7.57(4 H m), 7.68(1H, d, J = 2.4Hz), 8.02(1H, dd, J = 8.1,1.7Hz), 8.64(1H, d, J = 1.7Hz), 10.04(1H, brs), 10.52(1H, s), 10.81(1H,s). FAB-MS: 442(M + H)⁺ 13

NMR: δ1.33-1.45(2H, br), 1.46-1.57(4H, m), 1.84-1.93 (2H, m),2.43-2.69(7H, m), 2.84(3H, s), 3.19(2H, t, J = 5.6Hz), 3.94(2H, brs),6.85(1H, d, J = 8.3Hz), 7.01-7.08 (2H, m), 7.39-7.54(6H, m), 8.02(1H, d,J = 7.3Hz), 8.21 (1H, s), 10.05(1H, s). FAB-MS: 440(M + H)⁺ 14

NMR: δ1.20-1.36(1H, m), 1.52-1.66(3H, m), 1.81-1.97 (2H, m),2.58-2.70(2H, m), 3.18-3.31(2H, m), 4.42(2 H d, J = 5.3Hz),7.39-7.46(2H, m), 7.47-7.59(4H, m), 7.73 (1H, t, J = 7.8Hz), 7.82(1H, t,J = 7.8Hz), 8.07-8.17(3 H m), 8.90(1H, s), 9.20(1H, s), 9.57(1H, s),10.21(1H, brs), 11.43(1H, s). FAB-MS: 422(M + H)⁺ 15

NMR: δ1.20-1.35(1H, m), 1.52-1.65(3H, m), 1.76-1.92 (2H, m),2.56-2.68(2H, m), 3.18-3.28(2H, m), 4.41(2 H d, J = 4.9Hz),7.41-7.46(2H, m), 7.48-7.60(4H, m), 7.85- 7.93(1H, m), 8.00(1H, d, J =7.3Hz), 8.02-8.22(3H, m), 8.93(1H, s), 9.10-9.18(1H, m), 9.21(1H, d, J =3.9Hz), 10.34(1H, brs), 11.112(1H, s). FAB-MS: 422(M + H)⁺ 16

NMR: δ1.03-1.95(6H, m), 2.21-2.74(1H, m), 2.96-3.04 (1H, m),3.18-3.50(1H, m), 3.96-4.05(1H, m), 4.10-4.40 (2H, br), 4.91-4.99(1H,m), 7.39-7.59(6H, m), 8.08 (2H, d, J = 8.3Hz), 8.15(1H, d, J = 8.8Hz),8.79(2H, brs), 9.41(1H, s), 10.00(1H, br), 10.26(1H, br), 10.89(1H, s,). FAB-MS: 442(M + H)⁺ 17

NMR: 1.95-2.09(1H, m), 2.32-2.52(1H, m), 2.86-2.99 (1H, m),3.24-3.38(2H, m), 3.56-3.68(1H, m), 4.49(2 H d, J = 5.4Hz),5.45-5.55(1H, m), 5.70-5.80(1H, m), 7.39- 7.58(6H, m), 8.02(1H, d, J =8.8, 2.0Hz), 8.10(1H, dd, J = 7.8, 1.5Hz), 8.16(1H, d, J = 8.3Hz),8.70-8.80(2H, m), 9.41(1H, s), 10.55(1H, brs), 10.81(1H, s). FAB-MS:426(M + H)⁺

TABLE 14 Ex Structure(salt) DATA 18

NMR: δ2.75-2.85(1H, m), 3.07-3.26(2H, m), 3.47-3.59 (1H, m),3.98-4.08(1H, m), 4.27-4.36(1H, m), 4.52- 4.64(2H, brs), 7.08(1H, d, J =7.3Hz), 7.13(1H, d, J = 7.4Hz), 7.15-7.25(2H, m), 7.53(5H, m), 7.56(1H,d, J = 8.3Hz), 7.97(1H, d, J = 8.8Hz), 8.14(2H, d, J = 8.8Hz),8.73(2H.s.), 9.40(1H, s), 10.77(2H, brs). FAB-MS: 476(m + H)⁺ 19

NMR: δ1.72-1.91(4H, m), 2.70-2.82(2H, m), 3.33-3.42 (2H, m), 4.48(2H, d,J = 5.9Hz), 7.39-7.58(6H, m), 8.03-8.11(2H, m), 8.15(1H, d, J = 8.8Hz),8.74-8.82(2H, m), 9.42(1H, s), 10.78-10.89(2H, m). FAB-MS: 414 (M + H)⁺20

NMR: δ1.35-1.59(6H, m), 1.60-1.73(2H, m), 2.79-2.90 (2H, m),3.20-3.32(2H, m), 4.42(2H, d, J = 5.4Hz), 7.38-7.44(2H, m),7.47-7.58(4H, m), 8.03-8.11(2H, m), 8.16(1H, d, J = 8.8Hz), 8.79(2H, s),9.41(1H, s), 10.36 (1H, br), 10.83(1H, s). FAB-MS: 442(M + H)⁺ 21

NMR: δ2.73-2.90(2H, m), 3.25(2H, d, J = 12.3Hz), 3.72- 3.94(4H, m),4.00-4.60(2H, m), 7.36-7.58(6H, m), 8.01-8.11(2H, m), 8.15(1H, d, J =8.8Hz), 8.72-8.82 (2H, m), 9.41(1H, s), 10.74-10.89(2H, m). FAB-MS:430(M + H)⁺ 22

NMR: δ1.69-1.84(4H, m), 2.08-2.20(1H, m), 2.48-2.72 (1H, m),2.76-2.98(1H, m), 3.06-3.30(1H, m), 3.42- 3.71(1H, m), 3.30-4.60(3H, m),7.38-7.58(6H, m), 8.00-8.30(4H, m), 8.69(1H, d, J = 9.8Hz), 8.77(1H, d,J = 1.4Hz), 9.42(1H, s), 10.66-10.95(2H, m). FAB-MS: 471(M + H)⁺ 23

NMR: δ2.75(3H, m), 3.00-4.40(10H, m), 7.40-7.58 (6H, m), 7.95-8.08(2H,m), 8.15(1H, d, J = 8.8Hz), 8.49 (1H, brs), 8.73(1H, s), 9.41(1H, s),10.68(1H, s). FAB- MS: 443(M + H)⁺ 24

NMR: δ3.33-3.50(2H, m), 3.54-3.80(2H, m), 4.25-4.40 (2H, m), 4.49(2H, d,J = 5.4Hz), 4.52(2H, s), 6.82- 6.92(1H, m), 7.06-7.18(1H, m),7.38-7.57(6H, m), 7.77- 7.90(1H, m), 8.03-8.12(3H, m), 8.16(1H, d, J =8.8 Hz), 8.78-8.88(2H, m), 9.42(1H, s), 10.86(1H, s), 11.10 (1H, brs).FAB-MS: 506(M + H)⁺ 25

NMR: δ0.99(H, t, J = 7.3Hz), 2.76-2.89(2H, m), 2.97- 3.10(2H, m),4.43(2H, d, J = 5.3Hz), 7.42-7.59(6H, m), 8.04-8.11(2H, m), 8.15(1H, d,J = 8.8Hz), 8.74-8.81 (2H, m), 9.41(1H, s), 10.30(1H, brs), 10.89(1H,s). FAB-MS: 416(M + H)⁺ 26

NMR: δ1.00(3H, t, J = 7.3Hz), 2.78-3.28(7H, m), 3.57- 3.63(2H, m),4.44-4.60(2H, m), 7.39-7.59(6H, m), 8.04-8.11(2H, m), 8.15(1H, d, J =8.8Hz), 8.76-8.81(2H, m), 9.42(1H, s), 10.44(1H, brs), 10.87(1H, s).FAB- MS: 446(M + H)⁺

TABLE 15 Ex Structure(salt) DATA 27

NMR: δ1.01(3H, t, J = 7.3Hz), 2.60-2.78(1H, m), 2.79- 2.92(1H, m),4.20-4.60(4H, m), 7.35-7.62(11H, m), 8.04- 8.11(2H, m), 8.17(1H, d, J =8.8Hz), 8.73(1H, d, J = 1.4Hz), 8.80(1H, d, J = 1.9Hz), 9.42(1H, s),10.66(1H, brs), 10.90(1H, s). FAB-MS: 478(M + H)⁺ 28

NMR: δ3.11-3.22(10H, m), 3.50-3.63(4H, m), 4.60(2 H d, J = 4.9Hz),7.38-7.60(6H, m), 8.04(1H, dd ,J = 8.8, 1.9Hz), 8.11(1H, dd, J = 7.8,2.0Hz), 8.16(1H, d, J = 8.8 Hz), 8.70-8.80(2H, m), 9.42(1H, s),10.33(1H, brs), 10.82 (1H, s). FAB-MS: 476(M + H)⁺ 29

NMR: δ0.67-0.80(3H, m), 0.91-1.03(1H, m), 1.40-1.78 (3H, m),1.80-1.95(1H, m), 2.18-2.30(1H, m), 2.53- 3.30(2H, m), 4.33-4.60(2H, m),7.40-7.44(2H, m), 7.46-7.59(5H, m), 7.97(1H, dd, J = 8.8, 1.9Hz),8.13-8.19 (2H, m), 8.57(1H, s), 8.73(1H, d, J = 2.0Hz), 9.43(2 H s),10.63-10.67(1H, m). FAB-MS: 442(M + H)⁺ 30

NMR: δ0.70-0.86(3H, m), 1.30-1.72(5H, m), 2.57-2.70 (1.5H, m).2.88-3.04(0.5H, m), 3.20-3.29(2H, m), 4.37-4.59(2H, m), 7.39-7.60(6H,m), 7.93(1H, d, J = 8.3Hz), 8.14-8.19(2H, m), 8.50(1H, s), 8.71(1H, s),9.21 (0.8H, brs), 9.42(1H, m), 9.52(0.2H, brs), 10.63-10.67 (1H, m).FAB-MS: 442(M + H)⁺ 31

NMR: δ1.04-1.23(7H, m), 1.33-1.80(5H, m), 3.23-3.41 (1H, m),3.41-3.56(1H, m), 4.41(1.1H, s), 4.64(0.9 H s), 7.43-7.64(6H, m),7.90-7.97(1H, m), 8.10-8.19 (2H, m), 8.71(1H, s), 8.47(0.4H, brs),8.71(1H, s), 9.32 (0.6H, brs), 9.42(1H, s), 10.68-10.77(1H, m). FAB- MS:456(M + H)⁺ 32

NMR: δ0.63-0.80(7H, m), 1.07-1.19(0.2H, br), 1.41- 1.48(0.2H, m),1.58-1.67(0.8H, m), 1.76-1.91(1.8H, br), 2.09-2.21(2H, m),2.87-2.94(0.2H, m), 3.02-3.16 (1.8H, m), 4.42(1.8H, d, J = 5.4Hz),4.56-4.61(0.2H, m), 7.40-7.45(2H, m), 7.47-7.60(4H, m), 7.91(1H, dd, J =8.8, 2.0Hz), 8.14-8.21(2H, m), 8.44-8.50(1H, m), 8.70(1H, d, J = 2.0Hz),8.32-8.46(1.8H, m), 9.80(0.2 H brs), 10.64(1H, s). FAB-MS: 456(M + H)⁺33

NMR: δ0.92-1.24(10H, m), 1.26-1.56(3H, m), 1.62-1.74 (3H, brs),1.81-1.91(1H, m), 3.13-3.23(1H, m), 3.58- 3.68(1H, m), 4.41-4.57(2H, m),7.45-7.50(2H, m), 7.50-7.62(4H, m), 7.95(1H, d, J = 8.8Hz),8.13-8.18(2H, m), 8.36(1H, s), 8.44(1H, brs), 8.72(1H, d, J = 1.9Hz),9.42(1H, s), 10.74(1H, s). FAB-MS: 484(M + H)⁺ 34

NMR: δ1.24-1.32(1H, m), 1.54-1.62(3H, m), 1.74-1.88 (2H, m),2.48-2.52(2H, m), 3.18-3.24(2H, m), 4.37 (2H, d, J = 5.4Hz), 7.28(1H, d,J = 8.8Hz), 7.38-7.43(2 H m), 7.46-7.57(4H, m), 7.58-7.62(1H, m),7.87(1H, s), 8.02(1H, dd, J = 7.8, 1.4Hz), 8.69-8.72(1H, m), 10.11 (1H,brs), 10.66(1H, s), 11.68(1H, s). FAB-MS: 428 (M + H)⁺

TABLE 16 Ex Structure(salt) DATA 35

NMR: δ1.60-1.73(2H, m), 2.50-2.63(2H, m), 2.86-3.02 (2H, m),3.21-3.40(2H, m), 4.44-4.74(2H, m), 5.28-5.45 (1H, m), 7.00-7.61(11H,m), 8.01-8.19(3H, m), 8.70- 8.85(2H, m), 9.42(1H, s), 10.40-10.72(1H,m), 10.75- 10.96(1H, m). FAB-MS: 520(M + H)⁺ 36

NMR: δ1.20-1.34(1H, m), 1.52-1.63(3H, m), 1.73-1.89 (2H, m),2.53-2.65(2H, m), 3.17-3.24(2H, m), 4.37(2 H d, J = 4.9Hz), 6.02(2H, s),6.92(1H, d, J = 8.3Hz), 7.36- 7.42(3H, m), 7.45-7.56(5H, m), 8.00(1H, d,J = 8.3Hz), 8.70(1H, s), 10.14(1H, brs), 10.52(1H, s). FAB-MS: 415(M +H)⁺ 37

NMR: δ1.20-1.35(1H, m), 1.54-1.67(5H, m), 2.52-2.69 (2H, m),3.16-3.26(2H, m), 4.41(2H, d, J = 5.4Hz), 7.40- 7.45(2H, m),7.49-7.60(4H, m), 7.78(1H, brs), 8.12- 8.27(3H, m), 8.48(1H, s),8.80(1H, brs), 8.91(1H, s), 9.10 (1H, s), 9.22(1H, brs), 11.03(1H, s).FAB-MS: 422(M + H)⁺ 38

NMR: δ1.30-1.40(2H, m), 1.42-1.56(4H, m), 3.30-3.80 (6H, m), 7.09(1H, d,J = 7.7Hz), 7.40-7.52(7H, m), 7.85 (1H, d, J = 2.0Hz), 7.94-8.00(1H, m),8.15(1H, brs), 10.38 (1H, s), 11.60(1H, s). FAB-MS: 428(M + H)⁺ 39

NMR: δ1.20-1.35(1H, m), 1.53-1.63(3H, m), 1.74-1.90 (2H, m),2.54-2.66(2H, m), 3.18-3.24(2H, m), 3.33(3 H s), 4.38(2H, d, J = 5.4Hz,7.34(1H, d, J = 8.8Hz), 7.38- 7.42(2H, m), 7.46-7.57(4H, m), 7.63(1H,dd, J = 8.8, 1.9 Hz), 7.94(1H, d, J = 1.5Hz), 8.03(1H, dd, J = 8.8,1.4Hz), 8.74(1H, s), 10.17(1H, brs), 10.74(1H, s). FAB-MS: 442 (M + H)⁺40

NMR: δ1.20-1.35(1H, m), 1.53-1.65(3H, m), 1.72-1.88 (2H, m),2.56-2.69(2H, m), 3.19-3.25(2H, m), 4.39(2 H d, J = 5.4Hz),7.38-7.44(2H, m), 7.47-7.58(4H, m), 7.69 (1H,t, J = 8.3Hz),7.96-8.02(1H, m), 8.04-8.11(1H, m), 8.35(1H, d, J = 7.8Hz), 8.71(1H, s),8.95(1H, d, J = 2.0 Hz), 9.96(1H, brs), 11.11(1H, s). FAB-MS: 416(M +H)⁺ 41

NMR: δ1.20-1.35(1H, m), 1.52-1.66(5H, m), 2.55-2.68 (2H, m),3.17-3.24(2H, m), 4.39(2H, d, J = 4.9Hz), 7.33 (1H, d, J = 6.8Hz),7.39-7.44(2H, m), 7.48-7.58(4H, m), 7.61-7.66(2H, m), 8.04-8.09(1H, m),8.12-8.17(1 H m), 8.34(1H, s), 8.43(1H, s), 9.20(1H, brs), 10.85(1 H s).FAB-MS: 459(M + H)⁺ 42

NMR: δ1.20-1.35(1H, m), 1.56-1.64(3H, m), 1.72-1.86 (2H, m),2.54-2.63(2H, m), 2.68(2H, t, J = 5.4Hz), 3.09 (2H, t, J = 5.4Hz),3.18-3.24(2H, m), 4.37(2H, d, J = 5.4Hz), 7.38-7.45(2H, m),7.46-7.57(4H, m), 7.59(1H, d, J = 8.8Hz), 8.05(1H, dd, J = 8.8, 2.0Hz),8.16(1H, dd, J = 8.8, 2.0Hz), 8.29(1H, d, J = 1.9Hz), 8.71(1H, d, J =1.4Hz), 10.06 (1H, brs), 10.82(1H, s). FAB-MS: 425(M + H)⁺

TABLE 17 Ex Structure(salt) DATA 43

NMR: δ1.20-1.33(1H, m), 1.53-1.63(3H, m), 1.72-1.86 (2H, m),2.54-2.63(2H, m), 2.66-2.69(2H, m), 3.17- 3.24(4H, m), 4.38(2H, d, J =4.9Hz), 7.389-7.43(2 H m), 7.47-7.57(6H, m), 7.87(1H, d, J = 7.3Hz),8.07 (1H, dd, J = 7.8, 1.4Hz), 8.74(1H, s), 10.15(1H, brs), 10.48 (1H,s). FAB-MS: 425(M + H)⁺ 44

NMR: δ1.22-1.36(1H, m), 1.55-1.66(3H, m), 1.77-1.92 (2H, m),2.58-2.71(2H, m), 3.19-3.27(2H, m), 4.37 (2H, d, J = 5.4Hz),7.33-7.41(2H, m), 7.43-7.52(3H, m), 8.03-8.09(2H, m), 8.15(1H, d, J =8.8Hz), 8.75-8.80 (1H, m), 9.41(1H, s), 10.13(1H, brs), 10.88(1H, s).FAB-MS: 446(M + H)⁺ 45

NMR: δ1.21-1.34(1H, m), 1.53-1.63(3H, m), 1.76-1.90 (2H, m),2.54-2.65(2H, m), 3.19-3.25(2H, m), 4.38 (2H, d, J = 4.9Hz),6.37-6.41(1H, m), 7.28-7.57(9H, m), 8.00-8.07(1H, m), 8.21(1H, s),8.74(1H, s), 10.29 (1H, brs), 10.48(1H, s), 11.10(1H, s). FAB-MS: 410(M + H)⁺ 46

NMR: δ1.27-1.38(1H, m), 1.38-1.54(5H, m), 2.22(4 H brs), 3.33-3.42(2H,m), 7.23(1H, dd, J = 7.5, 2.3Hz), 7.34-7.54(7H, m), 7.84(1H, s),7.88-7.96(1H, m), 8.06(1H, d, J = 1.5Hz), 8.15(1H, s), 8.49(1H, d, J =6.9Hz), 10.49(1H, s). FAB-MS: 411(M + H)⁺ 47

NMR: δ1.21-1.35(1H, m), 1.54-1.64(3H, m), 1.77-1.92 (2H, m),2.56-2.68(2H, m), 3.17-3.29(2H, m), 4.41 (2H, d, J = 4.9Hz),7.38-7.45(2H, m), 7.47-7.58(4 H m), 8.05-8.15(2H, m), 8.39-8.46(1H, m),8.79-8.84 (2H, m), 8.86(1H, d, J = 2.0Hz), 8.93(1H, d, J = 2.0Hz),10.17(1H, brs), 1.15(1H, s). FAB-MS: 423(M + H)⁺ 48

NMR: δ1.20-1.36(1H, m), 1.52-1.65(3H, m), 1.79-1.96 (2H, m),2.55-2.70(2H, m), 3.18-3.37(8H, m), 4.39 (2H, d, J = 5.3Hz),7.37-7.63(7H, m), 7.85(1H, s), 7.97- 8.07(2H, m), 8.86(1H, d, J =1.5Hz), 10.14(1H, br s), 11.50(1H, s), 13.07(1H, brs). FAB-MS: 415(M +H)⁺ 49

NMR: δ1.16-1.35(1H, m), 1.50-1.66(3H, m), 1.74-1.97 (2H, m),2.54-2.65(2H, m), 2.77(3H, s), 2.85-2.97 (2H, m), 3.14-3.27(2H, m),3.33-3.542(2H, m), 4.37(2H, d, J = 4.4Hz), 7.09(1H, d, J = J = 8.3Hz),7.27-7.60(8 H m), 8.00(1H, d, J = 8.3Hz), 8.72(1H, s), 10.27(1H, brs),10.46(1H, s). FAB-MS: 426(M + H)⁺ 50

NMR: δ1.21-1.34(1H, m), 1.52-1.64(3H, m), 1.65-1.83 (2H, m), 2.17(3H,s), 2.55-2.60(2H, m), 3.06-3.28 (4H, m), 4.07-4.16(2H, m), 4.36(2H, d, J= 4.8Hz), 7.20 (1H, d, J = 8.3Hz), 7.37-7.57(7H, m), 8.06(1H, d, J =7.9Hz), 8.57(2H, s), 9.93(1H, brs), 10.45(1H, s). FAB- MS: 454(M + H)⁺

TABLE 18 Ex Structure(salt) DATA 51

NMR: δ1.20-1.35(1H, m), 1.52-1.64(3H, m), 1.80-1.95 (2H, m),2.53-2.66(2H, m), 3.19-3.25(2H, m), 3.44 (2H, s) 4.37(2H, d, J = 5.4Hz),7.15-7.19(1H, m), 7.38- 7.41(2H, m), 7.45-7.56(5H, m), 7.68(1H, brs),7.97- 8.01(1H, m), 8.78(1H, s), 10.46(2H, m), 10.62(1H, s). FAB-MS:426(M + H)⁺ 52

NMR(300 MHz, DMSO-d₆): δ1.20-1.37(1H, m), 1.52- 1.65(3H, m),1.77-1.95(2H, m), 2.54-2.69(2H, m), 3.17-3.28(2H, m), 4.39(2H, d, J =5.1Hz), 7.38-7.60(7H, m), 8.03(1H, dd ,J = 8.1, 1.7Hz), 8.43(1H, dd, J =8.6, 2.7Hz), 8.81(1H, d, J = 1.5Hz), 9.02(1H, d, J = 2.6Hz), 10.16(1H,brs), 11.10(1H, s). FAB-MS: 406(M + H)⁺ 53

NMR: δ1.20-1.32(1H, m), 1.53-1.63(3H, m), 1.78-1.90(2H, m),2.58-2.63(2H, m), 3.18-3.26(2H, m), 4.38 (2H, d, J = 5.2Hz),7.37-7.58(6H, m), 7.94-7.98(1H, m), 8.04(1H, dd, J = 7.8, 1.5Hz),8.11(1H, d, J = 2.3Hz), 8.35(1H, d, J = 5.3Hz), 8.76(1H, s), 10.02(1H,brs), 11.26 (1H, s). FAB-MS: 406(M + H)⁺ 54

NMR: δ1.20-1.36(1H, m), 1.52-1.64(3H, m), 1.77-1.93 (2H, m),2.54-2.68(2H, m), 3.02(3H, s), 3.16-3.28 (2H, m), 4.38(2H, d, J =4.8Hz), 7.34-7.57(7H, m), 7.77 (1H, dd, J = 8.8, 2.0Hz), 7.96-8.05(2H,m), 8.77(1H, s), 9.50(1H, s), 10.20(1H, brs), 10.89(1H, s). FAB-MS:482(M + H)⁺ 55

NMR: δ1.20-1.35(1H, m), 1.52-1.64(3H, m), 1.80-1.95 (2H, m),2.53-2.66(2H, m), 3.19-3.24(2H, m), 3.45 (2H, s), 4.37(2H, d, J =5.4Hz), 7.28-7.32(1H, m), 7.38- 7.41(2H, m), 7.45-7.56(5H, m),7.84-7.85(1H, m), 7.98-8.02(1H, m), 8.74-8.77(1H, m), 10.37(1H, br s),10.66(1H, s), 10.69(1H, s). FAB-MS: 458(M + H)⁺ 56

NMR(CDCl₃): δ1.30-1.61(6H, m), 2.20-2.50(4H, m), 3.44(2H, s), 5.09(2H,brs), 6.86(1H, s), 7.21-7.62 (8H, m), 7.71(1H, d, J = 8.4Hz), 7.88(1H,d, J = 8.3Hz), 8.19(1H, dd, J = 8.1, 1.8Hz), 8.51(1H, d, J = 1.6Hz).FAB-MS: 438(M + H)⁺ 57

NMR: δ1.20-1.35(1H, m), 1.52-1.64(3H, m), 1.77-1.94 (2H, m),2.53-2.68(2H, m), 3.10-3.40(2H, m), 4.39 (2H, d, J = 4.9Hz),6.77-6.85(1H, m), 7.24-7.58(8H, m), 7.95(1H, dd, J = 8.8, 2.0Hz),8.03-8.13(2H, m), 8.49 (1H, d, J = 2.0Hz), 8.79(1H, d, J = 2.6Hz),10.12(1H, s), 10.29(1H, brs), 10.78(1H, s). FAB-MS: 437(M + H)⁺ 58

NMR: δ1.20-1.35(1H, m), 1.52-1.64(3H, m), 1.80-1.95 (2H, m),2.55-2.66(2H, m), 3.19-3.26(2H, m), 3.35 (3H, s), 3.52(2H, s), 4.38(2H,d, J = 4.8Hz), 7.38-7.42 (3H, m), 7.46-7.56(4H, m), 7.74-7.79(1H, m),7.98- 8.04(2H, m), 8.78-8.82(1H, m), 10.25(1H, brs), 10.80- 10.81(1H,m). FAB-MS: 472(M + H)⁺

TABLE 19 Ex Structure(salt) DATA 59

NMR: δ1.20-1.35(1H, m), 1.52-1.64(3H, m), 1.80-1.95 (2H, m), 2.33(3H,s), 2.54-2.64(2H, m), 3.17-3.26(2 H m), 4.37(2H, d, J = 4.9Hz),7.19-7.23(1H, m), 7.36-7.42 (3H, m), 7.46-7.56(4H, m), 7.69(1H, brs),7.84-7.88 (1H, m), 7.98-8.02(2H, m), 8.77(1H, brs), 10.37(1H, m),10.66(1H, s). FAB-MS: 428(M + H)⁺ 60

NMR: δ1.20-1.35(1H, m), 1.52-1.64(3H, m), 1.76-1.90 (2H, m),2.42-2.48(2H, m), 2.54-2.64(2H, m), 2.81-2.87 (2H, m), 3.17-3.24(2H, m),4.37(2H, d, J = 5.4Hz), 7.12- 7.15(1H, m), 7.34-7.42(3H, m),7.46-7.56(4H, m), 7.64-7.66(1H, m), 7.99-8.03(1H, m), 8.71-8.74(1H, m),10.16(1H, s), 10.34(1H, brs), 10.55(1H, s). FAB- MS: 440(M + H)⁺ 61

NMR: δ1.27-1.52(6H, m), 2.16-2.34(4H, m), 3.39(2H, s), 7.11(1H, dd, J =8.8, 1.9Hz), 7.22(1H, dd, J = 2.0Hz), 7.28-7.52(8H, m), 7.75(1H, d, J =7.8Hz), 7.83(1H, d, J = 8.8Hz), 8.06(1H, d, J = 7.9Hz), 8.17(1H, s),9.75(1H, s), 10.32(1H, s). FAB-MS: 437(M + H)⁺ 62

NMR: δ1.20-1.30(1H, m), 1.54-1.64(3H, m), 1.84-1.97 (2H, m),2.54-2.66(2H, m), 3.16-3.28(2H, m), 4.39(2 H d, J = 5.4Hz), 5.00(2H,brs), 7.38-7.57(7H, m), 7.87- 8.93(1H, m), 8.00-8.05(1H, m),8.07-8.10(1H, m), 8.42- 8.45(1H, m), 8.82-8.87(1H, m), 10.40(1H, brs),10.68 (1H, s). FAB-MS: 411(M + H)⁺ 63

NMR: δ1.21-1.37(1H, m), 1.50-1.66(3H, m), 1.77-1.95 (2H, m),2.55-2.67(2H, m), 3.18-3.30(2H, m), 3.28(3 H s), 4.39(2H, m), 4.65(2H,s), 7.01(1H, d, J = 8.8Hz), 7.38- 7.58(6H, m), 7.67(1H, dd, J = 8.6,2.0Hz), 7.89(1H, d, J = 2.2Hz), 7.99-8.06(1H, m), 8.77-8.81(1H, m),10.24 (1H, brs), 10.69(1H, s). FAB-MS: 456(M + H)⁺ 64

NMR: δ1.20-1.35(1H, m), 1.52-1.64(3H, m), 1.76-1.92 (2H, m),2.54-2.65(2H, m), 3.18-3.26(2H, m), 4.38(2 H d, J = 5.4Hz),7.38-7.42(2H, m), 7.46-7.56(5H, m), 7.65- 7.70(1H, m), 8.00-8.04(2H, m),8.77(1H, s), 10.32 (1H, s), 10.76(1H, s), 11.96(1H, brs). FAB-MS:444(M + H)⁺ 65

NMR: δ1.20-1.35(1H, m), 1.52-1.65(3H, m), 1.80-1.95 (2H, m),2.56-2.66(2H, m), 3.20-3.26(2H, m), 3.40(3 H s), 4.39(2H, d, J = 5.4Hz),7.38-7.42(2H, m), 7.46-7.56 (4H, m), 7.60-7.64(1H, m), 7.80-7.86(1H, m),8.01- 8.05(1H, m), 8.07-8.10(1H, m), 8.80-8.82(1H, m), 10.29 (1H, s),10.86(1H, s). FAB-MS: 458(M + H)⁺ 66

NMR: δ1.22-1.33(1H, m), 1.54-1.62(3H, m), 1.73-1.88 (2H, m),2.55-2.65(2H, m), 3.18-3.24(2H, m), 4.38(2 H d, J = 4.9Hz),7.36-7.43(3H, m), 7.48-7.61(7H, m), 8.10-8.05(2H, m), 8.56(1H, s),8.74(1H, s), 10.19(1H, brs), 10.92(1H, s). FAB-MS: 450(M + H)⁺

TABLE 20 Ex Structure(salt) DATA 67

NMR: δ1.21-1.34(1H, m), 1.52-1.64(3H, m), 1.75-1.92 (2H, m),2.53-2.65(2H, m), 3.16-3.26(2H, m), 4.38 (2H, d, J = 5.4Hz),6.39-6.43(1H, m), 7.43-7.61(9H, m), 8.01-8.06(1H, m), 8.15(1H, s),8.75(1H, s), 10.32(1 H brs), 10.41(1H, s), 11.07(1H, s). FAB-MS: 410(M +H)⁺ 68

NMR: δ1.21-1.34(1H, m), 1.56-1.62(3H, m), 1.80-1.96 (2H, m),2.58-2.68(2H, m), 3.10-3.70(4H, m), 4.34- 4.44(2H, m), 7.38-7.58(6H, m),7.82-7.88(1H, m), 8.00-8.25(2H, m), 8.67(1H, s), 8.84-8.90(1H, m), 9.46-9.53(1H, m), 10.38(1H, brs), 11.06(1H, s). FAB-MS: 411(M + H)⁺ 69

NMR: δ1.19-1.35(1H, m), 1.52-1.63(3H, m), 1.72-1.89 (2H, m),2.55-2.63(2H, m), 3.02(3H, s), 3.07-3.11(2H, m), 3.18-3.22(2H, m),3.92-4.00(2H, m), 4.37(2H, d, J = 4.9Hz), 7.24(1H, d, J = 8.3Hz),7.36-7.59(7H, m), 8.00(1H, s), 8.04(1H, dd, J = 8.3, 1.5Hz), 8.70(1H,s), 10.19(1H, brs), 10.62(1H, s). FAB-MS: 490(M + H)⁺. 70

NMR: δ1.19-1.36(1H, m), 1.51-1.64(3H, m), 1.79-1.96 (2H, m),2.54-2.66(2H, m), 3.14-3.24(4H, m), 3.71- 3.75(2H, m), 4.38(2H, d, J =4.8Hz), 7.39-7.56(7H, m), 7.90(1H, d, J = 8.3Hz), 8.02(1H, dd, J = 7.8,1.5Hz), 8.14(1H, s), 8.81(1H, s), 10.32(1H, brs), 10.90(1H, s). FAB-MS:412(M + H)⁺ 71

NMR(CDCl₃): δ1.20-1.38(1H, m), 1.55-1.85(3H, m), 2.08-2.55(4H, m),3.35-3.52(8H, m), 4.49(2H, d, J = 5.1 Hz), 6.77(1H, d, J = 9.6Hz),7.25-7.55(5H, m), 8.02(1H, dd,J = 8.1, 1.5Hz), 8.57(1H, dd, J = 9.5,2.2Hz), 8.91 (1H, s), 9.16(1H, d, J = 2.2Hz), 10.50-10.72(2H, m),FAB-MS: 415(M + H)⁺ 72

NMR: δ1.20-1.33(1H, m), 1.53-1.64(3H, m), 1.80-1.95 (2H, m),2.55-2.68(2H, m), 3.18-3.30(2H, m), 4.40 (2H, d, J = 5.4Hz), 4.70(2H,brs), 7.38-7.58(6H, m), 7.94- 8.17(3H, m), 8.63(1H, s), 8.82-8.86(1H,m), 10.37 (1H, brs), 10.93(1H, s). FAB-MS: 412(M + H)⁺ 73

NMR: δ1.20-1.35(1H, m), 1.53-1.63(3H, m), 1.75-1.90 (2H, m),2.05-2.20(4H, m), 2.54-2.70(4H, m), 3.15- 3.26(2H, m), 4.37(2H, d, J =5.3Hz), 7.21-7.24(1H, m), 7.38-7.42(2H, m), 7.46-7.56(4H, m),7.58-7.62(1 H m), 7.68-7.72(1H, m), 7.99-8.03(1H, m), 8.70-8.72 (1H, m),9.60(1H, s), 10.23(1H, s), 10.61(1H, s). FAB- MS: 454(M + H)⁺ 74

NMR: δ1.20-1.35(1H, m), 1.53-1.63(3H, m), 1.80-1.95 (2H, m),2.00-2.10(2H, m), 2.14-2.22(2H, m), 2.55- 2.66(4H, m), 3.18-3.25(5H, m),4.37(2H, d, J = 4.9Hz), 7.23-7.27(1H, m), 7.38-7.42(2H, m), 7.46-7.56(4H m), 7.75-7.80(1H, m), 7.95-7.97(1H, m), 8.00-8.04 (1H, m), 8.79(1H,brs), 10.27(1H, s), 10.72(1H, s). FAB- MS: 468(M + H)⁺

TABLE 21 Ex Structure(salt) DATA 75

NMR: δ1.20-1.35(1H, m), 1.52-1.65(3H, m), 1.80-1.95 (2H, m),2.54-2.66(2H, m), 3.15-3.30(8H, m), 4.39 (2H, d, J = 4.9Hz),7.38-7.42(2H, m), 7.46-7.56(4H, m), 7.74-7.84(2H, m), 8.00-8.04(1H, m),8.22-8.30(1 H m), 8.76-8.84(1H, m), 10.31(1H, s), 10.79(1H, s). FAB-MS:471(M + H)⁺ 76

NMR: δ1.30-1.39(2H, m), 1.42-1.51(4H, m), 2.19-2.30 (4H, m), 3.38(2H,s), 3.86(3H, s), 6.75(1H, dd, J = 8.8, 2.4Hz), 7.38-7.49(6H, m),7.65(1H, s), 7.85-7.89(1H, m), 7.91(1H, d, J = 8.8Hz), 8.13(1H, d, J =1.5Hz), 8.27 (1H, s), 8.45(1H, d, J = 2.5Hz), 13.48(1H, s). FAB- MS:444(M + H)⁺ 77

NMR: δ1.29-1.39(2H, m), 1.39-1.49(4H, m), 2.17-2.28 (4H, m), 3.39(2H,s), 7.37-7.54(8H, m), 7.75-7.82(2H, m), 7.93(1H, d, J = 7.9Hz), 8.01(1H,d, J = 1.9Hz), 8.07 (1H, s), 10.52(1H, s). FAB-MS: 448(M + H)⁺ 78

NMR: δ1.20-1.35(1H, m), 1.52-1.64(3H, m), 1.76-1.92 (2H, m),2.52-2.65(4H, m), 2.80-2.87(2H, m), 3.12- 3.25(5H, m), 4.38(2H, d, J =4.9Hz), 7.18-7.22(1H, m), 7.36-7.42(2H, m), 7.44-7.56(4H, m),7.62-7.68(1H, m), 7.78(1H, s), 8.00-8.06(1H, m), 8.74(1H, s), 10.14 (1H,brs), 10.64(1H, s). FAB-MS: 454(M + H)⁺ 79

NMR: δ1.20-1.35(1H, m), 1.52-1.64(3H, m), 1.80-1.96 (2H, m),2.54-2.66(2H, m), 3.12(3H, s), 3.18-3.26(2H, m), 3.57(2H, s) 4.39(2H, d,J = 4.9Hz), 7.20-7.26(1H, m), 7.36-7.42(2H, m), 7.46-7.56(4H, m),7.58-7.62 (1H, m), 7.70-7.74(1H, m), 7.98-8.05(1H, m), 8.77- 8.82(1H,m), 10.36(1H, s), 10.69(1H, s). FAB-MS: 440(M + H)⁺ 80

NMR: δ1.20-1.35(1H, m), 1.52-1.64(3H, m), 1.80-1.95 (2H, m),2.54-2.66(2H, m), 3.18-3.26(2H, m), 3.77 (3H, s) 4.38(2H, d, J = 4.9Hz),6.39(1H, d, J = 2.9Hz), 7.28- 7.30(1H, m), 7.38-7.42(2H, m),7.46-7.60(6H, m), 8.01-8.06(1H, m), 8.20(1H, s), 8.80(1H, s), 10.39(1 Hbrs), 10.57(1H, s). FAB-MS: 424(M + H)⁺ 81

NMR: δ1.28(7H, brs), 1.52-1.64(3H, m), 1.80-1.95(2 H m), 2.54-2.66(2H,m), 3.14(3H, s), 3.18-3.26(2H, m), 4.38(2H, d, J = 5.3Hz), 7.30-7.34(1H,m), 7.38-7.42 (2H, m), 7.46-7.56(4H, m), 7.58-7.64(1H, m), 7.73 (1H, m),8.00-8.04(1H, m), 8.81(1H, s), 10.38(1H, br s), 10.69(1H, s). FAB-MS:468(M + H)⁺ 82

NMR: δ1.18-1.33(1H, m), 1.52-1.67(5H, m), 2.53-2.65 (2H, m),3.14-3.20(2H, m), 4.37(2H, d, J = 4.9Hz), 7.40- 7.46(2H, m),7.47-7.59(4H, m), 7.67-7.72(1H, m), 7.97-8.01(2H, m), 8.03(1H, d, J =2.5Hz), 8.40-8.44 (1H, m), 8.57(1H, s), 8.71(1H, d, J = 9.3Hz), 9.72(1H,brs), 12.95(1H, s). FAB-MS: 448(M + H)⁺

TABLE 22 Ex Structure(salt) DATA 83

NMR: δ1.20-1.34(1H, m), 1.42(3H, d, J = 6.8Hz), 1.53- 1.62(3H, m),1.71-1.86(2H, m), 2.53-2.65(2H, m), 3.14- 3.24(2H, m), 4.37(2H, d, J =5.4Hz), 4.63(1H, q, J = 6.9 Hz), 6.95(1H, d, J = 8.3Hz), 7.34-7.42(3H,m), 7.45-7.57 (4H, m), 7.68(1H, d, J = 2.4Hz), 7.99-8.05(1H, m), 8.65(1H, s), 10.08(1H, brs), 10.52(1H, s,), 10.75(1H, s). FAB-MS: 456(M +H)⁺ 84

NMR: δ1.21-1.35(1H, m), 1.40(6H, s), 1.52-1.63(3H, m), 1.74-1.91(2H, m),2.54-2.65(2H, m), 3.15-3.26(2 H m), 4.37(2H, d, J = 5.4Hz), 6.93(1H, d,J = 8.3Hz), 7.34- 7.43(3H, m), 7.45-7.57(4H, m), 7.68-7.72(1H, m), 7.98-8.03(1H, s), 8.68-8.73(1H, m), 10.26(1H, brs), 10.55 (1H, s), 10.70(1H,s). FAB-MS: 470(M + H)⁺ 85

NMR: δ1.20-1.34(1H, m), 1.44(3H, d, J = 6.8Hz), 1.52- 1.63(3H, m),1.77-1.92(2H, m), 2.54-2.67(2H, m), 3.18- 3.25(2H, m), 3.28(3H, m),4.38(2H, d, J = 5.4Hz), 4.71 (1 H, q, J = 6.6Hz), 7.02(1H, d, J =6.8Hz), 7.40(2H, d, J = 7.3Hz), 7.45-7.57(4H, m), 7.62-7.67(1H, m),7.86(1H, d, J = 1.9Hz), 8.03(1H, d, J = 8.8Hz), 8.75(1H, s,) 10.15 (1H,brs), 10.65(1H, s). FAB-MS: 470(M + H)⁺ 86

NMR: δ1.22-1.34(1H, m), 1.42(6H, s), 1.52-1.64(3H, m), 1.78-1.94(2H, m),2.55-2.67(2H, m), 3.17-3.26(2 H m), 3.29(3H, s), 4.38(2H, d, J = 4.9Hz),6.99(1H, d, J = 8.8Hz), 7.37-7.43(2H, m), 7.45-7.57(4H, m), 7.63-7.69(1H, m), 7.86(1H, d, J = 1.9Hz), 7.98-8.05(1H, m), 8.78 (1H, s),10.23(1H, brs), 10.66(1H, s). FAB-MS: 484(M + H)⁺ 87

NMR: δ1.25(7H, brs), 1.52-1.64(3H, m), 1.78-1.92(2 H m), 2.53-2.66(2H,m), 3.18-3.25(2H, m), 4.38(2H, d, J = 5.4Hz), 7.22-7.26(1H, m),7.38-7.42(2H, m), 7.46- 7.57(5H, m), 7.65-7.66(1H, m), 7.98-8.03(1H, m),8.73- 8.75(1H, s), 10.32(1H, brs), 10.40(1H, s), 10.58(1H, s). FAB-MS:454(M + H)⁺ 88

NMR: δ1.20-1.36(1H, m), 1.50-1.65(3H, m), 1.78-1.96 (2H, m),2.55-2.69(2H, m), 2.98(3H, s), 3.15-3.28(2 H m), 4.38(2H, d, J = 5.4Hz),7.36-7.58(6H, m), 8.02(1 H dd, J = 7.8, 1.5Hz), 8.44(1H, s), 8.64(1H, d,J = 3.5Hz), 8.81(1H, d, J = 1.5Hz), 10.15(1H, brs), 10.92(1H, s). FAB-MS: 435(M + H)⁺ 89

NMR: δ1.07(6H, s), 1.20-1.35(1H, m), 1.53-1.62(3H, m), 1.74-1.88(2H, m),2.53-2.65(2H, m), 2.72(2H, s), 3.18- 3.25(2H, m), 4.38(2H, d, J =5.4Hz), 7.10-7.15(1H, m), 7.33-7.42(3H, m), 7.46-7.57(4H, m),7.61-7.63(1 H m), 7.98-8.04(1H, m), 8.68-8.70(1H, m), 10.10(1H, brs),10.24(1H, s), 10.53(1H, s). FAB-MS: 468(M + H)⁺ 90

NMR: δ1.21-1.36(1H, m), 1.54-1.64(3H, m), 1.76-1.92 (2H, m),2.56-2.66(2H, m), 3.19-3.26(2H, m), 4.38(2 H d, J = 5.4Hz),7.02-7.07(1H, m), 7.38-7.57(6H, m), 8.02 (1H, dd, J = 8.1, 2.0Hz),8.05-8.11(1H, m), 8.28(1H, d, J = 1.5Hz), 8.78(1H, d, J = 1.5Hz),10.18(1H, brs), 10.84 (1H, s), 11.23(1H, brs) FAB-MS: 462(M + H)⁺

TABLE 23 Ex Structure(salt) DATA 91

NMR: δ1.80-2.38(4H, m), 2.40-2.48(2H, m), 2.65-2.90 (4H, m),3.18-3.32(2H, m), 4.36-4.50(2H, m), 4.60-5.02 (1H, m), 7.10-7.17(1H, m),7.32-7.37(1H, m), 7.38- 7.42(2H, m), 7.46-7.56(4H, m), 7.60-7.64(1H, m),8.00- 8.04(1H, m), 8.62-8.67(1H, m), 10.17(1H, s), 10.04- 10.53(2H, m).FAB-MS: 458(M + H)⁺ 92

NMR: δ1.88-2.34(4H, m), 2.52-2.58(2H, m), 2.72-2.88 (4H, m),3.24-3.27(5H, m), 4.38-4.49(2H, m), 4.60-5.20 (1H, m), 7.18-7.23(21 ,m), 7.38-7.42(2H, m), 7.46- 7.56(4H, m), 7.62-7.68(1H, m), 7.74-7.78(1H,m), 8.01- 8.06(1H, m), 8.65-8.70(1H, m), 10.34(1H, s), 10.59(1H, s).ESI-MS: 472(M + H)⁺ 93

NMR: δ1.50-1.80(2H, br), 1.80-2.10(2H, br), 2.42-2.48 (2H, m),2.52-2.55(1H, m), 2.80-2.2.88(3H, m), 3.85- 4.75(4H, br), 7.10-7.17(1H,m), 7.28-7.33(1H, m), 7.40- 7.55(8H, m), 7.98-8.08(1H, m), 8.51(1H, br),10.18(1H, s), 10.42(1H, brs). FAB-MS: 476(M + H)⁺ 94

NMR: δ1.50-2.25(4H, br), 2.52-2.56(4H, m), 2.82-2.86 (2H, m),3.22-3.75(5H, m), 4.20-5.00(2H, br), 7.17-7.23 (1H, m), 7.41-7.57(6H,m), 7.58-7.62(1H, m), 7.74(1H, s), 8.02-8.09(1H, m), 8.50-8.80(1H, br),10.59(1H, brs), 10.80-11.20(1H, br). FAB-MS: 490(M + H)⁺ 95

NMR: δ1.11(6H, t, J = 5.9Hz), 1.30-1.50(2H, m), 1.50-1.64 (4H, m),2.55-3.00(4H, m), 3.49(4H, q, J = 14.2, 6.9 Hz), 4.20(2H, brs), 6.62(1H,d, J = 9.3Hz), 7.37-7.56(6 H m), 7.84(1H, dd, J = 9.3, 2.9Hz), 8.06(1H,dd, J = 7.9, 1.5 Hz), 8.39(1H, s), 8.42(1H, d, J = 2.5Hz), 10.22(1H, s).FAB-MS: 443(M + H)⁺. 96

NMR: δ1.20-1.65(12H, m), 2.48-2.85(4H, m), 3.44-3.52 (4H, m), 4.02(2H,s), 6.85(1H, d, J = 9.2Hz), 7.38-7.55 (6H, m), 7.89(1H, dd, J = 8.8,2.5Hz), 8.00-8.07(1H, m), 8.28(1H, s), 8.47(1H, d, J = 2.9Hz), 10.25(2H,s). FAB- MS: 455(M + H)⁺ 97

NMR: δ1.30-1.59(6H, m), 2.48-2.75(4H, m), 3.83-4.06 (5H, m), 6.87(1H, d,J = 8.8Hz), 7.37-7.55(6H, m), 8.01- 8.11(2H, m), 8.28(1H, s), 8.56(1H,d, J = 2.9Hz), 10.43 (1H, m). FAB-MS: 402(M + H)⁺ 98

NMR: δ1.30-1.47(2H, m), 1.47-1.62(4H, m), 2.55-2.81 (7H, m),3.50-4.70(2H, m), 6.50(1H, d, J = 8.8Hz), 7.37- 7.56(6H, m), 7.76(1H,dd, J = 8.8, 2.4Hz), 8.04(1H, d, J = 7.8Hz), 8.31(1H, s), 8.35(1H, d, J= 2.4Hz), 10.17(1 H s). FAB-MS: 401(M + H)⁺ 99

ESI-MS: 411(M + H)⁺

TABLE 24 Ex Structure(salt) DATA 100

NMR: δ1.60-2.05(4H, m), 2.18-2.90(3H, m), 3.08-3.38 (2H, m),4.34-4.46(2H, m), 6.86(1H, brs), 7.24-7.58 (7H, m), 8.04-8.18(3H, m),8.76-8.81(2H, m), 9.41(1H, s), 10.17-10.52(1H, m), 10.89(1H, s). FAB-MS:471 (M + H)⁺ 101

NMR: δ0.98-1.36(5H, m), 1.50-1.60(1H, m), 1.62-1.73 (2H, m),1.82-1.92(2H, m), 2.80-2.95(1H, m), 4.17- 4.26(2H, m), 7.44-7.58(6H, m),8.00-8.18(3H, m), 8.67-8.79(2H, m), 9.22(2H, brs), 9.41(1H, s), 10.81(1H, brs). FAB-MS: 442(M + H)⁺ 102

NMR: δ0.81(3H, d, J = 6.8Hz), 1.17(3H, d, J = 6.8Hz), 2.95- 3.85(8H, m),4.45-4.59(2H, m), 7.42-7.60(6H, m), 8.01-8.18(3H, m), 8.67-8.79(2H, m),9.41(1H, s), 9.74 (1H, brs), 10.90(1H, brs). FAB-MS: 460(M + H)⁺ 103

NMR: δ1.48-2.14(4H, m), 2.60-2.86(2H, m), 3.02-3.90 (2H, m),4.25-4.45(3H, m), 4.45-4.59(2H, m), 7.36- 7.58(6H, m), 8.02-8.18(3H, m),8.77-8.88(2H, m), 9.42(1H, s), 10.32-10.53(1H, m), 10.87-10.94(1H, m).FAB-MS: 444(M + H)⁺ 104

NMR: δ0.90-1.09(6H, m), 1.33-1.70(2H, m), 1.72-2.10 (2H, m),2.65-3.02(3H, m), 3.12-3.34(6H, m), 4.34- 4.51(2H, m), 7.36-7.70(6H, m),8.01-8.18(3H, m), 8.74-8.84(2H, m), 9.42(1H, s), 10.28(1H, brs), 10.88(1H, s). FAB-MS: 527(M + H)⁺ 105

NMR: δ1.73-2.14(4H, m), 2.60-2.80(2H, m), 3.06-3.52 (6H, m),4.38-4.45(2H, m), 7.37-7.58(6H, m), 8.02- 8.18(3H, m), 8.78-8.85(2H, m),9.41(1H, s), 10.50(1H, brs), 10.86-10.92(1H, m). FAB-MS: 458(M + H)⁺ 106

NMR: δ1.11-2.00(4H, m), 2.48-2.85(2H, m), 3.02-3.58 (6H, m),4.25-4.58(2H, m), 7.38-7.59(6H, m), 7.92- 8.22(3H, m), 8.62-8.84(2H, m),9.40-9.43(1H, m), 10.56(1H, brs), 10.73-10.88(1H, m). FAB-MS: 458(M +H)⁺ 107

NMR(CDCl₃): δ1.10-1.91(10H, m), 2.37-3.20(9H, m), 3.36-3.54(2H, m),7.27-7.47(6H, m), 7.84-7.97(3H, m), 8.12(1H, d, J = 1.8Hz), 8.48(1H, s),8.74-9.03(2H, m). FAB-MS: 511(M + H)⁺ 108

NMR: δ1.30-2.45(10H, m), 2.70-3.52(9H, m), 4.35-4.63 (2H, m),7.38-7.59(6H, m), 8.03-8.18(3H, m), 8.74- 8.86(1H, m), 9.42(1H, s),10.65-10.98(2H, m). FAB-MS: 511(M + H)⁺

TABLE 25 Ex Structure(salt) DATA 109

NMR: δ2.85-3.00(2H, m), 3.34-3.50(4H, m), 3.65-3.75 (2H, m),4.50-4.60(2H, m), 7.06(1H, dd, J = 7.8, 4.4Hz), 7.40-7.58(6H, m),7.82(1H, dd, J = 7.8, 1.4Hz), 8.02- 8.24(4H, m), 8.75-8.82(2H, m),9.41(1H, s), 10.73(1H, brs), 10.85(1H, s). FAB-MS: 540(M + H)⁺ 110

NMR: δ1.89-2.40(4H, m), 2.70-2.90(2H, m), 3.17-3.40 (2H, m),4.38-4.52(2H, m), 4.58-5.04(1H, m), 7.36-7.58 (6H, m), 8.01-8.18(3H, m),8.76-8.86(2H, m), 9.42 (1H, s), 10.68(1H, brs), 10.83-10.92(1H, m).FAB-MS: 446(M + H)⁺ 111

NMR: δ1.55-2.10(4H, m), 2.46-5.00(6H, m), 7.40-7.58 (6H, m),7.94-8.18(3H, m), 8.48-8.79(2H, m), 9.41(1 H s), 10.79(2H, brs). FAB-MS:464(M + H)⁺ 112

NMR: δ1.20-1.35(1H, m), 1.53-1.65(3H, m), 1.78-1.94 (2H, m),2.55-2.67(2H, m), 3.15-3.25(2H, m), 3.43(3 H s), 4.38(2H, d, J = 5.4Hz),4.80(2H, s), 7.38-7.42(2 H m), 7.46-7.57(4H, m), 7.88-7.92(1H, m),8.03-8.12 (2H, m), 8.25(1H, s), 8.81(1H, s), 10.08(1H, brs), 11.17 (1H,s). FAB-MS: 504(M + H)⁺ 113

NMR: δ1.21-1.35(1H, m), 1.55-1.65(3H, m), 1.74-1.91 (2H, m),2.56-2.68(2H, m), 3.20-3.28(2H, m), 4.40(2 H d, J = 4.9Hz),7.40-7.67(9H, m), 8.02-8.22(4H, m), 8.58- 8.80(3H, s), 10.11(1H, brs),10.96(1H, s). FAB-MS: 500(M + H)⁺ 114

NMR: δ1.20-1.35(1H, m), 1.52-1.64(3H, m), 1.72-1.86 (3H, m),2.31-2.40(1H, m), 2.57-2.62(2H, m), 2.64- 2.73(1H, m), 2.84-2.92(1H, m),3.16-3.24(2H, m), 4.37 (2H, d, J = 4.9Hz), 5.04(1H, t, J = 6.4Hz),5.27(1H, br s), 7.20(1H, d, J = 8.3Hz), 7.37-7.42(2H, m), 7.45-7.56 (4H,m), 7.69(1H, dd, J = 8.8, 2.0Hz), 7.94(1H, s), 8.03 (1H, dd, J = 8.8,2.0Hz), 8.66(1H, s), 10.11(1H, brs), 10.50 (1H, s). FAB-MS: 427(M + H)⁺115

NMR: δ0.87(12H, t, J = 6.6Hz), 1.92-2.04(2H, m), 2.68- 2.74(4H, m),4.55(2H, d, J = 5.4Hz), 7.43-7.47(2H, m), 7.48-7.60(4H, m),8.04-8.10(1H, m), 8.13-8.18(2 H m), 8.79(1H, s), 8.86(1H, brs), 9.42(1H,s), 9.54(1H, brs), 10.95(1H, s). FAB-MS: 472(M + H)⁺ 116

NMR: δ0.94-1.02(3H, m), 1.06-1.14(3H, m), 2.52-2.58 (2H, m),2.78-3.08(4H, m), 3.10-3.40(9H, m), 3.90-3.98 (1H, m), 4.00-4.14(1H, m),4.45-4.65(2H, m), 4.80- 4.92(1H, br), 7.18-7.22(1H, m), 7.36-7.44(2H,m), 7.46-7.58(4H, m), 7.62-7.68(1H, m), 7.79(1H, brs), 7.98- 8.04(1H,m), 8.74(1H, br), 10.56(1H, s), 11.04(1H, br). FAB-MS: 555(M + H)⁺

TABLE 26 Ex Structure(salt) DATA 117

NMR: δ1.02-1.20(6H, m), 2.52-2.58(2H, m), 2.60-2.72 (1H, m),2.80-2.90(2H, m), 2.90-3.04(1H, m), 3.26(3 H s), 3.28-3.70(5H, m),3.73-3.83(1H, m), 3.88-3.98(1H, m), 4.00-4.10(1H, m), 4.15-4.28(1H, br),4.33-4.45 (1H, m), 4.62-5.12(1H, br), 7.18-7.22(1H, m), 7.38-7.42 (2H,m), 7.44-7.58(4H, m), 7.58-7.62(1H, m), 7.77 (1H, brs), 8.05-8.12(1H,m), 8.42(1H, s), 10.00-10.55 (1H, br), 10.80(1H, s). FAB-MS: 555(M + H)⁺118

NMR: δ0.93-1.01(3H, m), 1.04-1.12(3H, m), 1.35-1.50 (1H, m),1.56-1.76(3H, m), 1.90-2.05(1H, m), 2.52-2.58 (2H, m), 2.62-2.72(1H, m),2.76-2.88(3H, m), 3.08- 3.28(8H, m), 3.42-3.54(1H, m), 4.42-4.52(2H, m),7.18- 7.24(1H, m), 7.34-7.44(2H, m), 7.46-7.60(4H, m), 7.64-7.68(1H, m),7.82-7.84(1H, m), 7.98-8.12(1H, m), 8.79(1H, s), 10.52(1H, br),10.64(1H, s). FAB-MS: 553(M + H)⁺ 119

NMR: δ0.86-0.92(6H, m), 1.57-1.84(3H, m), 1.95-2.08 (1H, m),2.36-2.44(1H, m), 2.52-2.58(2H, m), 2.80-2.88 (2H, m), 2.90-2.98(1H, m),3.08-3.23(4H, m), 3.27 (3H, s), 3.43-3.48(1H, m), 3.63-3.77(2H, m),7.18-7.22 (1H, m), 7.34-7.37(1H, m), 7.38-7.52(6H, m), 7.63(1 H s),7.85-7.91(1H, m), 8.14(1H, s), 10.23(1H, s). FAB- MS: 539(M + H)⁺ 120

NMR: δ1.30-1.50(1H, m), 1.60-1.90(3H, m), 2.52-2.58 (2H, m),2.60-2.70(1H, br), 2.82-2.95(4H, m), 3.15-3.27 (4H, m), 3.37-3.48(1H,m), 4.35-4.70(2H, m), 7.18- 7.24(1H, m), 7.37-7.42(2H, m), 7.47-7.58(5H,m), 7.65 (1H, s), 8.07-8.18(1H, m), 8.48(1H, brs), 9.48-9.66 (1H, br),10.40(1H, s). FAB-MS: 522(M + H)⁺ 121

NMR: δ0.80(3H, t, J = 7.3Hz), 1.15-1.25(1H, m), 1.40- 1.52(3H, m),1.60-1.70(2H, m), 1.84-1.94(1H, m), 2.00 (2H, t, J = 7.3Hz),2.04-2.20(1H, m), 2.52-2.58(2H, m), 2.62-2.81(2H, m), 2.82-2.88(2H, m),3.26(3H, s), 3.64-3.80(3H, br), 7.18-7.24(1H, m), 7.38-7.52(7H, m),7.59-7.65(2H, m), 7.95-8.02(1H, m), 8.17(1H, s), 10.34 (1H, s). FAB-MS:539(M + H)⁺ 122

NMR: δ0.88(3H, d, J = 6.4Hz), 1.25-1.45(4H, m), 1.42 (3H, d, J = 6.9Hz),1.50-1.63(1H, m), 1.65-1.73(3H, m), 1.83-1.93(2H, m), 2.04-2.12(1H, m),2.55-2.62(1 H m), 2.77-2.95(3H, m), 3.07-3.19(1H, m), 3.20-3.33 (2H, m),3.52(2H, s), 4.63(1H, q, J = 6.8Hz), 6.95(1H, d, J = 8.3Hz), 7.27(1H,dd, J = 8.8, 2.5Hz), 7.37-7.55(7H, m), 7.92(1H, dd,J = 6.8, 2.0Hz),8.06(1H,d, J = 2.0Hz), 10.27(1H, s), 10.75(1H, s). FAB-MS: 553(M + H)⁺123

NMR: δ0.81(3H, t, J = 6.8Hz), 1.04(6H, s), 1.42(3H, d, J = 6.4Hz),2.36(2H, brs), 2.90-4.20(3H, m), 3.82(2H, br s), 4.63(1H, q, J = 6.8Hz),6.94(1H, d, J = 8.8Hz), 7.25(1 H dd, J = 8.8, 2.5Hz), 7.31-7.38(3H, m),7.39-7.52(3H, m), 7.58(1H, d, J = 2.4Hz), 7.91(1H, d, J = 7.7Hz, 8.28(1H, s), 10.24(1H, s), 10.71(1H, s). FAB-MS: 488(M + H)⁺

TABLE 27 Ex Structure (salt) DATA 124

NMR: δ 1.21 (3H, t, J = 6.8Hz), 1.18-1.34 (1H, m), 1.52- 1.66 (3H, m),1.76-1.94 (2H, m), 2.50-2.65 (4H, m), 2.78- 2.85 (2H, m), 3.18-3.25 (2H,m), 3.88 (2H, q, J = 6.8Hz), 4.38 (2H, d, J = 5.3Hz),7.20 (1H, d, J =5.3Hz), 7.35- 7.58 (6H, m), 7.65-7.72 (1H, m), 7.85 (1H, s), 7.95-8.07(1H, m), 8.79 (1H, s), 10.23 (1H, brs), 10.67 (1H, s). FAB-MS: 468 (M +H)⁺ 125

NMR: δ 1.21-1.34 (1H, m), 1.54-1.64 (3H, m), 1.72-1.86 (2H, m),2.55-2.63 (4H, m), 2.82-2.89 (2H, m), 3.18- 3.26 (2H, m), 4.20 (2H, dt,J = 22.9, 5.4Hz), 4.38 (2H, d, J = 5.4Hz), 4.67 (2H, dt, J = 47.4,5.4Hz), 7.22 (1H, d, J = 8.3Hz), 7.37-7.57 (6H, m), 7.63 (1H, ddd, J =7.8, 2.0, 1.5Hz), 7.84 (1H, d, J = 1.5Hz), 8.05 (1H, ddd, J = 7.8, 2.0,1.5Hz), 8.70 (1H, d, J = 1.5Hz), 9.99 (1H, brs), 10.60 (1H, s). FAB-MS:486 (M + H)⁺ 126

NMR: δ 1.20-1.35 (1H, m), 1.52-1.66 (3H, m), 1.70-1.85 (2H, m),2.53-2.67 (2H, m), 3.16-3.23 (2H, m), 4.38 (2H, d, J = 5.3Hz), 6.39 (1H,dd, J = 9.3, 2.0Hz), 7.35-7.66 (8H, m), 7.84 (1H, d = 9.3Hz), 8.06 (1H,dd, J = 8.3, 1.5Hz), 8.17 (1H, s), 8.68 (1H, s), 10.05 (1H, brs), 10.82(1H, s), 11.78 (1H, s). FAB-MS: 438 (M + H)⁺ 127

NMR: δ 1.20-1.37 (1H, m), 1.53-1.66 (3H, m), 1.70-1.85 (2H, m), 2.12(3H, s), 2.55-2.70 (2H, m), 3.20-3.29 (2H, m), 3.63 (3H, s), 4.40 (2H,d, J = 5.4Hz), 7.36-7.58 (6H, m), 7.63 (1H, d, J = 8.8Hz), 7.74 (1H, s),7.95 (1H, dd, J = 8.8, 1.4Hz), 8.04 (1H, dd, J = 7.8, 1.5Hz), 8.28 (1H,d, J = 1.0Hz), 8.85 (1H, s), 10.32 (1H, brs), 10.96 (1H, s). FAB-MS: 466(M + H)⁺ 128

NMR: δ 1.13 (3H, d, J = 6.9Hz), 1.20-1.34 (1H, m), 1.52- 1.64 (3H, m),1.72-1.89 (2H, m), 2.45-2.65 (4H, m), 2.91 (1H , dd, J = 15.7, 5.9Hz),3.19 (2H, d, J = 11.7Hz), 4.37 (2H, d, J = 5.4Hz), 7.13 (1H, d, J =8.3Hz), 7.32-7.58 (7H, m), 7.59 (1H, d, J = 1.9Hz), 8.00 (1H, dd, J =8.3, 1.5Hz), 8.68 (1H, d, J = 1.5Hz), 10.15 (1H, s), 10.21 (1H, brs),10.53 (1H, s). FAB-MS: 454 (M + H)⁺ 129

NMR: δ 1.19-1.30 (1H, m), 1.53-1.66 (3H, m), 1.80-1.97 (2H, m),2.55-2.69 (2H, m), 3.23-3.26 (2H, m), 3.61 (3H, s), 4.40 (2H, d, J =4.9Hz), 6.52 (1H, d, J = 9.3Hz), 7.36- 7.58 (6H, m), 7.72 (1H, d, J =8.3Hz), 7.86 (1H, d, J = 9.3Hz), 7.97 (1H, dd, J = 8.3, 1.4Hz), 8.05(1H, dd, J = 8.3, 1.4Hz), 8.32 (1H, d, J = 1.4Hz), 8.84 (1H, d, J =1.4Hz), 10.25 (1H, brs), 11.01 (1H, s). FAB-MS: 452 (M + H)⁺ 130

NMR: δ 1.20-1.35 (1H, m), 1.50-1.65 (3H, m), 1.80-1.95 (2H, m), 2.08(3H, s), 2.45-2.67 (2H, m), 3.23 (2H, d, J = 11.2Hz), 4.39 (2H, d, J =5.4Hz), 6.52 (1H, d, J = 9.3Hz), 7.36-7.66 (8H, m), 8.03 (1H, dd, J =1.4, 7.8Hz), 8.21 (1H, d, J = 1.5Hz), 8.80 (1H, d, J = 1.4Hz), 10.42(1H, br s), 10.83 (1H, s), 11.78 (1H, s). FAB-MS: 452 (M + H)⁺

TABLE 28 Ex Structure (salt) DATA 131

NMR: δ 1.23-1.31 (1H, m), 1.52-1.78 (5H, m), 2.46-2.64 (4H, m),2.89-2.94 (2H, m), 3.16-3.23 (2H, m), 4.37 (2H, d, J = 5.4Hz), 7.06 (1H,s), 7.38-7.43 (3H, m), 7.47-7.57 (4H, m), 8.08 (1H, dd, J = 7.9, 1.9Hz),8.59 (1H, d, J = 1.9Hz), 9.90 (1H, brs), 10.23 (1H, s), 10.29 (1H, s).FAB-MS: 474 (M + H)⁺ 132

NMR: δ 1.20-1.35 (1H, m), 1.52-1.64 (3H, m), 1.80-1.94 (2H, m),2.56-2.68 (2H, m), 2.91 (6H, s), 3.16-3.26 (2H, m), 4.39 (2H, d, J =5.3Hz), 4.74 (1H, brs), 7.36-7.42 (2H, m), 7.46-7.58 (4H, m), 8.02 (1H,dd, J = 8.3, 1.5Hz), 8.40 (1H, d, J = 2.0Hz), 8.77 (1H, d, J = 2.5Hz),8.80-8.84 (1H, m), 10.22 (1H, brs), 10.91 (1H, s). FAB-MS: 449 (M + H)⁺133

NMR: δ 1.20-1.35 (1H, m), 1.50-1.65 (3H, m), 1.80-1.95 (2H, m), 2.08(3H, s), 2.45-2.67 (2H, m), 3.23 (2H, d, J = 11.2Hz), 4.39 (2H, d, J =5.4Hz), 6.52 (1H, d, J = 9.3Hz), 7.36-7.66 (8H, m), 8.03 (1H, dd, J =1.4, 7.8Hz), 8.21 (1H, d, J = 1.5Hz), 8.80 (1H, d, J = 1.4Hz), 10.42(1H, br s), 10.83 (1H, s), 11.78 (1H, s). FAB-MS: 452 (M + H)⁺ 134

NMR: δ 1.21-1.34 (1H, m), 1.53-1.64 (3H, m), 1.76-1.90 (2H, m),2.54-2.66 (2H, m), 3.18-3.26 (2H, m), 3.62 (2H, s), 4.38 (2H, d, J =5.2Hz), 7.38-7.43 (2H, m), 7.47-7.57 (5H, m), 7.90 (2H, d, J = 2.4Hz),8.03 (1H, dd, J = 8.1, 1 .7Hz), 8.72 (1H, d, J = 1.5Hz), 10.11 (1H,brs), 10.83 (1H, s), 10.93 (1H, s). FAB-MS: 494 (M + H)⁺ 135

NMR: δ 1.22-1.34 (1H, m), 1.52-1.65 (3H, m), 1.79-1.94 (2H, m),2.56-2.68 (2H, m), 3.19 (3H, s), 3.18-3.26 (2H, m), 4.39 (2H, d, J =4.9Hz), 7.28 (1H, d, J = 8.3Hz), 7.38- 7.43 (2H, m), 7.47-7.57 (4H, m),8.03 (1H, d, J = 7.8Hz), 8.18 (1H, d, J = 7.8Hz), 8.34 (1H, m), 8.79(1H, m), 10.20 (1H, brs), 10.91 (1H, s). FAB-MS: 476 (M + H)⁺ 136

NMR: δ 0.92 (3H, t, J = 7.4Hz), 1.20-1.40 (1H, m), 1.54- 1.75 (7H, m),2.50-2.90 (6H, m), 3.10-3.25 (2H, m), 3.70- 3.85 (2H, m), 4.38 (2H, d, J= 5.4Hz), 6.52 (1H, d, J = 9.3Hz), 7.21 (2H, d, J = 8.3Hz), 7.37-7.61(5H, m), 7.77 (1H, s), 8.08 (1H, m), 8.58 (1H, s), 9.71 (1H, brs), 10.54(1H, s). FAB-MS: 468 (M + H)⁺ 137

NMR: δ 1.34-1.47 (1H, m), 1.64-1.86 (5H, m), 2.52-2.58 (2H, m),2.80-2.88 (2H, m), 2.88-3.00 (2H, m), 3.19-3.25 (2H, m), 3.24 (3H, s),3.34-3.42 (2H, m), 3.44-3.51 (2H, m), 7.19 (1H, d, J = 8.3Hz), 7.41-7.47(2H, m), 7.50-7.58 (3H, m), 7.66-7.78 (5H, m), 9.89 (1H, brs), 10.51(1H, s). FAB-MS: 468 (M + H)⁺

TABLE 29 Ex Structure (salt) DATA 138

NMR: δ 1.30-1.44 (2H, brm), 1.48-1.60 (4H, brm), 2.54- 2.70 (4H, brm),2.90 (6H, s), 3.90-4.08 (2H, m), 7.40- 7.55 (6H, m), 8.06 (1H, d, J =8.3Hz), 8.31 (1H, brs), 8.46- 8.49 (1H, m), 8.85 (1H, d, J = 1.9Hz),10.62-10.68 (1H, brm). FAB-MS: 483 (M + H)⁺ 139

NMR: δ 1.22-1.35 (1H, m), 1.56-1.66 (3H, m), 1.76-1.90 (2H, m),2.53-2.68 (4H, m), 2.81-2.89 (2H, m), 3.26 (3H, s), 3.26-3.37 (2H, m),4.14 (2H, d, J = 5.4Hz), 7.22 (1H, d, J = 7.8Hz), 7.31-7.36 (2H, m),7.49-7.59 (3H, m), 7.64 (1H, dd, J = 8.3, 1.9Hz), 7.74 (1H,d, J =1.9Hz), 8.18 (1H, s), 8.72 (1H, d, J = 1.9Hz), 10.03 (1H, brs), 10.69(1H, s). FAB-MS: 488 (M + H)⁺ 140

NMR: δ 0.98 (6H, s), 1.58 (2H, t, J = 7.3Hz), 2.45-2.63 (4H, m),2.80-3.02 (4H, m), 3.26 (3H, s), 4.07 (2H, brs) , 7.20 (1H, d, J =7.8Hz), 7.43-7.55 (7H, m), 7.60 (1H, s), 8.04 (1H, d, J = 7.8Hz), 8.24(1H, s) 10.37 (1H, s). FAB-MS: 468 (M + H)⁺ 141

NMR: δ 1.20-1.34 (1H, m), 1.42 (3H, d, J = 6.8Hz), 1.53- 1.62 (3H, m),1.71-1.86 (2H, m), 2.53-2.65 (2H, m), 3.14- 3.24 (2H, m) 4.37 (2H, d, J= 5.4Hz), 4.63 (1H, q, J = 6.9Hz), 6.95 (1H, d, J = 8.3Hz), 7.34-7.42(3H, m), 7.45-7.57 (4H, m), 7.68 (1H, d, J = 2.4Hz), 7.99-8.05 (1H, m),8.65 (1H, s), 10.08 (1H, brs), 10.52 (1H, s,), 10.75 (1H, s). FAB-MS:456 (M + H)⁺ 142

NMR: δ 1.20-1.34 (1H, m), 1.42 (3H, d, J = 6.8Hz), 1.53- 1.62 (3H, m),1.71-1.86 (2H, m), 2.53-2.65 (2H, m), 3.14- 3.24 (2H, m), 4.37 (2H, d, J= 5.4Hz), 4.63 (1H, q, J = 6.9Hz), 6.95 (1H, d, J = 8.3Hz), 7.34-7.42(3H, m), 7.45-7.57 (4H, m), 7.68 (1H, d, J = 2.4Hz), 7.99-8.05 (1H, m),8.65 (1H, s), 10.08 (1H, brs), 10.52 (1H, s,), 10.75 (1H, s). FAB-MS:456 (M + H)⁺ 143

NMR: δ 0.97 (6H, t, J = 7.0Hz), 2.73-2.89 (2H, m), 2.94- 3.10 (2H, m),3.62 (2H, s), 4.35-4.45 (2H, m), 7.38-7.46 (2H, m), 7.47-7.59 (4H, m),7.83-7.94 (2H, m), 7.99-8.07 (1H, m), 8.67 (1H, s), 10.15 (1H, brs),10.82 (1H, s), 10.85-10.93 (1H, m). FAB-MS: 482 (M + H)⁺ 144

NMR: δ 2.53-2.58 (2H, m), 2.75-2.88 (4H, m), 3.19-3.27 (5H, m),3.70-3.90 (4H, m), 4.40-4.50 (2H, m), 7.19-7.22 (1H, m), 7.38-7.42 (2H,m), 7.46-7.56 (4H, m), 7.62- 7.66 (1H, m), 7.75 (1H, s), 8.02-8.07 (1H,m), 8.68 (1H, s), 10.57 (1H, s), 10.69 (1H, brs). FAB-MS: 456 (M + H)⁺145

NMR: δ 2.52-2.60 (2H, m), 2.80-2.88 (2H, s), 3.13 (3H, s), 3.13-3.22(4H, m), 3.36 (6H, s), 3.56-3.65 (4H, m), 4.59 (2H, d , J = 4.9Hz) ,7.20 (1H, d , J = 8.3Hz), 7.38-7.60 (6H, m) 7.66 (1H, dd, J = 8.3,1.5Hz), 7.80 (1H, s), 8.06 (1H, d, J = 8.3Hz), 8.77 (1H, s), 10.46 (1H,brs), 10.60 (1H, s). FAB-MS: 502 (M + H)⁺

TABLE 30 Ex Structure (salt) DATA 146

NMR: δ 0.98 (3H, t, J = 7.3Hz), 2.57-2.60 (2H, m), 2.80- 2.90 (2H, m),2..80-3.40 (6H, m), 3.15 (3H, s), 3.26 (3H, s), 3.52-3.65 (2H, m),4.40-4.60 (2H, m), 7.20 (1H, d, J = 8.3Hz), 7.37-7.60 (6H, m), 7.66 (1H,dd, J = 7.8, 1.5Hz), 7.82 (1H, d, J = 1.5Hz), 8.04 (1H, d, J = 7.8Hz),8.76 (1H, s), 10.44 (1H, brs), 10.63 (1H, s). FAB-MS: 472 (M + H)⁺ 147

NMR: δ 0.88-1.00 (3H, m), 1.36-1.56 (1H, m), 1.90-2.05 (1H, m),2.15-2.40 (2H, m), 2.52-2.75 (2H, m), 2.80-3.00 (3H, m), 3.25 (3H, s),3.36-3.50 (2H, m), 4.44-4.52 (2H, m), 7.18-7.22 (1H, m), 7.38-7.43 (2H,m), 7.46-7.58 (4H, m), 7.64-7.70 (1H, m), 7.80 (1H, s), 8.00-8.04 (1H,m), 8.70-8.74 (1H, m), 10.56 (1H, s), 10.75-10.95 (1H, br). FAB-MS: 454(M + H)⁺ 148

NMR: δ 1.10-1.26 (1H, m), 1.45-2.00 (5H, m), 2.54-2.57 (2H, m),2.69-2.86 (3H, m), 3.06-3.79 (2H, m), 3.21 (3H, s), 3.25 (3H, s),4.27-4.32, 4.61-4.54 (2H, m), 7.19- 7.22 (1H, m), 7.35-7.75 (7H, m),7.82 (1H, s), 7.99, 8.01 (1H, d, J = 8.3Hz), 8.62, 8.78 (1H, s),9.50-10.65 (2H, m). FAB-MS: 484 (M + H)⁺ 149

NMR: δ 0.87-0.98 (3H, m), 1.35-1.54 (1H, m), 1.90-2.05 (1H, m),2.10-2.47 (3H, m), 2.70-3.00 (5H, m), 3.34-3.50 (1H, m), 4.42-4.50 (2H,m), 7.12-7.16 (1H, m), 7.32- 7.37 (1H, m), 7.38-7.43 (2H, m), 7.46-7.57(4H, m), 7.60 (1H, s), 7.99-8.05 (1H, m), 8.61 (1H, brs), 10.17 (1H, s),10.43 (1H, s), 10.74 (1H, brs). FAB-MS: 440 (M + H)⁺ 150

NMR: δ 1.20-1.34 (1H, m), 1.53-1.64 (3H, m), 1.71-1.86 (2H, m),2.54-2.66 (2H, m), 2.87 (6H, s), 3.17-3.23 (2H, m), 4.38 (2H, d, J =5.4Hz), 7.37-7.57 (6H, m), 8.05 (1H, dd, J = 7.8, 2.0Hz), 8.50 (1H, d, J= 2.4Hz), 8.69 (1H, d, J = 1.5Hz), 8.77 (1H, d, J = 2.4Hz), 9.91 (1H,brs), 10.79 (1H, s). FAB-MS: 493, 495 (M + H)⁺ 151

NMR: δ 0.79 (3H, d, J = 6.8Hz), 1.39 (3H, d, J = 6.4Hz), 1.46- 1.56 (1H,m), 1.58-1.70 (1H, m), 1.96-2.12 (1H, m), 2.18-2.32 (1H, m), 2.53-2.58(2H, m), 2.82-2.88 (2H, m), 3.26 (3H, s), 3.42-3.52 (1H, m), 3.64-3.74(1H, br), 4.08-4.4.17 (1H, m), 4.66-4.77 (1H, m), 7.18-7.22 (1H, m),7.38-7.46 (2H, m), 7.48-7.60 (4H, m), 7.66-7.72 (1 H, m), 7.82-7.86 (1H,m), 8.05-8.10 (1H, m), 9.00 (1H, s), 10.26 (1H, brs), 10.58 (1H, s).FAB-MS: 468 (M + H)⁺ 152

NMR: δ 0.84-1.10 (3H, m), 1.78-2.06 (2H, m), 2.52-2.58 (2H, m),2.77-2.98 (4H, m), 3.15-3.22 (2H, m), 3.25 (3H, s), 3.35-3.50 (2H, m),4.07 (1H, br), 4.40-4.60 (2H, m), 7.18-7.22 (1H, m), 7.38-7.44 (2H, m),7.46-7.58 (4H, m), 7.58-7.70 (1H, m), 7.74-7.82 (1H, m), 7.99-8.09 (1H,m), 8.65-8.75 (1H, m), 10.51 (1H, s), 11.12 (1H, s). 484 (M + H)⁺

TABLE 31 Ex Structure (salt) DATA 153

NMR: δ 1.02 (6H, d, J = 6.4Hz), 2.28-2.38 (2H, m), 2.52- 2.58 (2H, m),2.82-2.88 (2H, m), 3.18-3.26 (5H, m), 3.95- 4.14 (2H, m), 4.37-4.52 (2H,m), 7.18-7.22 (1H, m), 7.38- 7.44 (2H, m), 7.46-7.58 (4H, m), 7.60-7.70(1H, m), 7.78 (1H, brs), 8.00-8.08 (1H, m), 8.72 (1H, br), 10.50- 10.60(1H, m), 10.98 (1H, br). FAB-MS: 484 (M + H)⁺ 154

NMR: δ 1.23-1.35 (1H, m), 1.55-1.67 (3H, m), 1.67-1.78 (2H, m),2.53-2.58 (2H, m), 2.60-2.71 (2H, m), 2.81-2.88 (2H, m), 3.19-3.27 (5H,m), 4.37 (2H, d, J = 5.4Hz), 7.19- 7.26 (2H, m), 7.30-7.37 (2H, m),7.50-7.63 (3H, m), 7.71 (1H, s), 8.03 (1H, d, J = 7.8Hz), 8.60 (1H, s),9.74 (1H, brs), 10.58 (1H, s). FAB-MS: 472 (M + H)⁺ 155

NMR: δ 1.05-1.17 (6H, m), 1.40-1.57 (2H, m), 1.60-1.76 (2H, m),1.78-1.96 (2H, m), 2.36-2.44 (1H, m), 2.52-2.58 (2H, m), 2.82-2.88 (2H,m), 2.91-2.99 (1H, m), 3.26 (3H, s), 3.27-3.40 (3H, br), 3.46-3.54 (1H,m), 4.00-4.14 (1H, m), 4.32-4.40 (1H, m), 4.50-4.60 (1H, m), 7.18-7.24(1H, m), 7.36-7.42 (2H, m), 7.44-7.60 (5H, m), 7.73 (1H, s), 8.06-8.12(1H, m), 8.38 (1H, s), 9.67-9.80 (1H, m), 10.72 (1H, brs). FAB-MS: 553(M + H)⁺ 156

NMR: δ 1.33 (3H, d, J = 6.4Hz), 1.54-1.90 (3H, m), 2.00- 2.10 (1H, m),2.52-2.58 (2H, m), 2.60-2.72 (1H, m), 2.82- 2.88 (2H, m), 3.26 (3H, s),3.28-3.38 (2H, m), 4.12-4.24 (1H, m), 4.70-4.80 (1H, m), 7.18-7.24 (1H,m), 7.38- 7.46 (2H, m), 7.46-7.60 (4H, m), 7.62-7.68 (1H, m), 7.76- 7.84(1H, m), 8.00-8.08 (1H, m), 8.64-8.72 (1H, m), 10.27 (1H, br), 10.59(1H, s). FAB-MS: 454 (M + H)⁺ 157

NMR: δ 1.20-1.33 (1H, m), 1.50-1.63 (3H, m), 1.78-1.92 (2H, m),2.58-2.68 (2H, m), 3.14-3.28 (2H, m), 4.38 (2H, d, J = 5.4Hz), 3.85-5.25(3H, brm), 7.40 (2H, d, J = 6.9Hz), 7.44-7.56 (4H, m), 8.00 (1H, dd, J =8.3, 1.5Hz), 8.47 (1H, d, J = 2.0Hz), 8.61 (1H, d, J = 2.0Hz), 8.78 (1H,s), 10.08 (1H, brs), 10.94 (1H, s). FAB-MS: 421 (M + H)⁺ 158

1.24-1.34 (1H, m), 1.50-1.65 (3H, m), 1.75-1.93 (2H, m), 2.56-2.69 (2H,m), 3.14-3.26 (2H, m), 4.03 (3H, br s), 4.38 (2H, d, J = 5.4Hz),7.34-7.56 (6H, m), 8.02 (1H, d dd, J = 7.8, 2.0, 1.5Hz), 8.60 (1H, d, J= 2.0Hz), 8.64 (1H, d, J = 2.0Hz), 8.77 (1H, d, J = 1.5Hz), 10.06 (1H,brs), 10.92 (1H, s). FAB-MS: 467 (M + H)⁺ 159

NMR: δ 1.45-1.60 (1H, m), 1.60-1.75 (2H, m), 1.80-2.00 (1H, m),2.35-2.48 (1H, br), 2.52-2.58 (2H, m), 2.82- 2.88 (2H, m), 2.90-3.02(1H, br), 3.05-3.22 (5H, m), 3.26 (3H, s), 3.30-3.40 (1H, br), 3.75-4.00(1H, br), 4.30-4.50 (1H, m), 7.18-7.22 (1H, m), 7.38-7.58 (7H, m) , 7.64(1H, s), 7.95-8.10 (1H, m), 8.25 (1H, s), 10.39 (1H, s). FAB-MS: 484 (M+H)⁺

TABLE 32 Ex Structure (salt) DATA 160

NMR: δ 1.20-1.34 (1H, m), 1.54-1.65 (3H, m), 1.74-1.87 (2H, m),2.52-2.68 (4H, m), 2.80-2.87 (2H, m), 3.16-3.27 (5H, m), 4.34 (2H, d, J= 5.3Hz), 7.20 (1H, d, J = 8.3Hz), 7.33-7.40 (2H, m), 7.42-7.50 (3H, m),7.64 (1H, dd, J = 8.8, 2.0Hz), 7.96 (1H, d, J = 1.9Hz), 8.04 (1H, dd, J= 8.8, 2.0Hz), 8.69 (1H, s), 9.98 (1H, s), 10.62 (1H, s). FAB- MS: 472(M + H)⁺ 161

NMR: δ 1.20-1.37 (1H, m), 1.54-1.68 (3H, m), 1.76-1.96 (2H, m),2.60-2.72 (4H, m), 2.78-2.90 (2H, m), 3.16-3.36 (5H, m), 4.27-4.42 (2H,m), 7.20 (1H, d, J = 8.3Hz), 7.38- 7.52 (3H, m), 7.52-7.62 (2H, m),7.64-7.71 (1H, m), 7.76-7.84 (1H, m), 7.95-8.07 (1H, m), 8.77 (1H, s),10.17 (1H, brs), 10.63-10.73 (1H, m). FAB-MS: 488 (M)⁺ 162

NMR: δ 1.18-1.37 (1H, m), 1.50-1.69 (3H, m), 1.79-1.97 (2H, m),2.52-2.72 (4H, m), 2.79-2.90 (2H, m), 3.18-3.28 (5H, m), 4.26-4.42 (2H,m), 7.20 (1H, d, J = 8.3Hz), 7.53 (1H, d, J = 7.8Hz), 7.64-7.90 (6H, m),8.03-8.10 (1H, m), 8.78-8.87 (1H, m), 10.24 (1H, brs), 10.66-10.75 (1H,m). FAB-MS: 522 (M + H)⁺ 163

NMR: δ 1.25-1.42 (1H, m), 1.54-1.72 (3H, m), 1.78-1.97 (2H, m),2.52-2.59 (2H, m), 2.60-2.90 (4H, m), 3.17-3.49 (5H, m), 4.46-4.60 (2H,m), 7.13-7.35 (3H, m), 7.56- 7.69 (2H, m), 7.73-7.85 (2H, m), 7.95-8.07(1H, m), 8.77 (1H, brs), 10.26 (1H, brs), 10.61-10.71 (1H, m). FAB- MS:460 (M + H)⁺ 164

NMR: δ 1.20-1.38 (1H, m), 1.52-1.69 (3H, m), 1.78-1.97 (2H, m),2.52-2.74 (4H, m), 2.78-2.89 (2H, m), 3.17-3.28 (5H, m), 4.28-4.43 (2H,m), 7.20 (1H, d, J = 7.9Hz), 7.32- 7.40 (1H, m), 7.44-7.60 (4H, m),7.64-7.72 (1H, m), 7.76-7.83 (1H, m), 7.97-8.06 (1H, m), 8.80 (1H, s),10.20 (1H, brs), 10.64-10.73 (1H, m). FAB-MS: 488 (M)⁺ 165

NMR: δ 1.90-2.06 (10H, m), 2.50-3.30 (7H, m), 3.32-3.40 (m, 6H), 3.26(3H, s), 4.10-4.24, 4.38-4.54 (2H, m), 7.16-7.24 (1H, m), 7.34-7.68 (7H,m), 7.79 (1H, s), 8.02, 8.06 (1H, d, J = 8.3Hz), 8.55, 8.72 (1H, s),9.15, 10.28 (1H, brs), 10.40, 10.60 (1H, s). FAB-MS: 565 (M)⁺ 166

NMR: δ 1.42 (3H, d, J = 6.8Hz), 2.73-2.85 (2H, m), 3.17- 3.26 (2H, m),3.73-3.88 (4H, m), 4.41-4.49 (2H, m), 4.63 (1H, d, J = 6.8Hz), 6.96 (1H,d, J = 8.3Hz), 7.33-7.42 (3H, m), 7.45-7.57 (4H, m), 7.68 (1H, s), 8.02(1H, d, J = 7.8Hz), 8.65 (1H, s), 10.49 (1H, s), 10.75 (1H, s),10.71-10.86 (1H, br). FAB-MS: 458 (M + H)⁺ 167

NMR: δ 1.79-2.25 (4H, m), 2.50-2.90-(9H, m), 3.26 (3H, s), 4.38, 4.51(2H, s), 7.21 (1H, d, J = 8.3Hz), 7.44-7.70 (7H, m), 8.05 (1H, d, J =7.8Hz), 7.74 (1H, s), 8.63 (1H, s), 10.22 (1H, brs), 10.56 (1H, s).FAB-MS: 479 (M)⁺

TABLE 33 Ex Structure (salt) DATA 168

NMR: δ 1.36-1.60 (6H, m), 2.56-2.73 (4H, m), 2.98 (3H, s), 2.99 (3H, s),3.75-6.30 (4H, brm), 7.41-7.54 (6H, m), 7.97 (1H, dd, J = 15.1, 2.0Hz),8.04 (1H, ddd, J = 7.8, 2.0, 1.5Hz), 8.29 (1H, s), 8.39 (1H, m), 10.49(1H, s). FAB-MS: 433 (M + H)⁺ 169

NMR: δ 0.77 (3H, t, J = 7.4Hz), 1.03-1.10 (6H, m), 2.50- 2.60 (2H, m),2.67-2.73 (1H, m), 2.83-2.87 (2H, m), 2.87- 3.00 (1H, m), 3.18-3.41 (4H,m), 3.26 (3H, s), 4.35, 4.44 (2H, m), 4.46-4.55 (2H, m), 7.22 (1H, d, J= 8.3Hz), 7.40- 7.59 (7H, m), 7.66 (1H, s), 8.11 (1H, d, J = 8.3Hz),8.52 (1H, s), 9.55 (1H, brs), 10.50 (1H, s). FAB-MS: 527 (M + H)⁺ 170

NMR: δ 1.03 (3H, t, J = 7.3Hz), 1.36 (1H, d, J = 11.7Hz), 1.64- 1.80(2H, m), 2.06 (1H, d, J = 11.7Hz), 2.50-2.57 (2H, m), 2.83-2.96 (4H, m),3.13 (1H, t, J = 11.7Hz), 3.24- 3.34 (2H, m), 3.25 (3H, s), 3.76 (1H, d,J = 7.9Hz), 3.87 (1H, d, J = 7.9Hz), 4.34 (1H, dd, J = 13.6, 6.3Hz),4.65 (1H, dd, J = 13.6, 4.9Hz), 7.20 (1H, d, J = 7.9Hz), 7.42-7.58 (6H,m), 7.66 (1H, dd, J = 8.3, 2.0Hz), 7.83 (1H, d, J = 7.9Hz), 8.03 (1H,dd, J = 8.3, 1.5Hz), 8.71 (1H, dd, J = 1.5Hz), 10.23 (1H, brs), 10.69(1H, s). FAB-MS: 498 (M + H)⁺ 171

NMR: δ 1.02-1.07 (1H, m), 1.57-1.69 (2H, m), 1.85-2.00 (1H, m),2.28-2.44 (2H, m), 2.50-2.58 (2H, m), 2.83-2.86 (2H, m), 3.02-3.06 (1H,m), 3.17-3.47 (5H, m), 3.19 (3H, s), 3.25 (3H, s), 4.35-4.47 (2H, m),7.20 (1H, d, J = 8.3Hz), 7.34-7.58 (6H, m), 7.66 (1H, dd, J = 8.3,1.9Hz), 7.80 (1H, d, J = 2.0Hz), 8.02 (1H, dd, J = 8.3, 2.0Hz), 8.78(1H, dd, J = 2.0Hz), 10.40 (1H, brs), 10.66 (1H, s). FAB- MS: 498 (M +H)⁺ 172

NMR: δ 1.28-1.45 (1H, br), 1.55-2.00 (9H, m), 2.28-2.42 (1H, br),2.52-2.58 (2H, m), 2.80-2.88 (2H, m), 2.90- 3.00 (2H, br), 3.13-3.23(2H, m), 3.25 (3H, s), 3.48-3.58 (2H, br), 3.94-4.12 (2H, m), 4.14-4.32(1H, m), 5.06-5.18 (1H, m), 7.18-7.22 (1H, m), 7.34-7.42 (2H, m), 7.48-7.58 (4H, m), 7.65-7.73 (1H, s), 7.80 (1H, s), 7.98-8.05 (1H, s), 8.79(1H, s), 10.50 (1H, s), 10.92 (1H, s), 11.11 (1H, s). FAB-MS: 537 (M +H)⁺ 173

NMR: δ 1.30-1.44 (2H, m), 1.46-1.56 (4H, m), 2.32-2.69 (2H, m),3.10-4.05 (4H, m), 4.65 (2H, s), 7.12 (1H, s), 7.20 (1H, s), 7.40-7.54(6H, m), 8.00-8.09 (1H, m), 8.23 (1H, s), 10.05 (1H, s), 10.90 (1H, s).FAB-MS: 476 (M + H)⁺ 174

NMR: δ 0.97 (3H, t, J = 7. 3Hz), 2. 08 (3H, s), 2.75-3.50 (4H, m), 3.16(3H, s), 3.57 (2H, s), 4.44-4.55 (2H, d, m), 7.42 (2H, d, J = 6.8Hz),7.46-7.62 (6H, m), 7.71 (1H, s), 8.07 (1H, d, J = 7.8Hz), 8.13 (1H, s),8.65 (1H, s), 10.15 (1H, brs), 10.48 (1H, s), 11.78 (1H, s). FAB-MS: 470(M + H)⁺

TABLE 34 Ex Structure (salt) DATA 175

NMR: δ 1.39-1.74 (10H, m), 2.08 (3H, s), 2.49-3.37 (9H, m), 4.15-4.21,4.45-4.49 (2H, m), 7.30-7.62 (8H, m), 7.71 (1H, s), 7.90-8.16 (2H, m),8.54, 8.67 (1H, s), 9.13, 10.23 (1H, brs), 10.56, 10.73 (1H, s), 11.78,11.80 (1H, s). FAB-MS: 563 (M + H)⁺ 176

NMR: δ 1.20-1.33 (1H, m), 1.43 (3H, d, J = 6.8Hz), 1.55- 1.64 (3H, m),1.70-1.84 (2H, m), 2.58-2.70 (2H, m), 3.16- 3.26 (2H, m), 4.34 (2H, d, J= 4.9Hz), 4.64 (1H, q, J = 6.8Hz), 6.96 (1H, d, J = 8.8Hz), 7.36 (1H,dd, J = 8.8, 2.5Hz), 7.35 (1H, d, J = 8.3Hz), 7.64-7.68 (1H, m),7.70-7.80 (3H, m), 7.87 (1H, d, J = 7.4Hz), 8.06 (1H, d, J = 7.8Hz),8.65 (1H, brs), 9.96 (1H, brs), 10.54 (1H, s), 10.76 (1H, s). FAB-MS:524 (M + H)⁺ 177

NMR: δ 1.00-1.12 (1H, m), 1.16-1.29 (2H, m), 1.29-1.42 (2H, m), 1.42(3H, d, J = 6.8Hz), 1.55-1.64 (1H, m), 1.74- 1.84 (2H, m), 2.01-2.10(2H, m), 2.32-2.42 (2H, m), 2.76- 2.86 (2H, m), 2.86-2.99 (2H, m),3.03-3.13 (1H, m), 2.80-3.37 (2H, m), 3.52 (2H, s), 4.63 (1H, q, J =6.8Hz), 6.95 (1H, d, J = 8.8Hz), 7.28 (1H, dd, J = 8.8, 2.4Hz), 7.38-7.55 (7H, m), 7.94 (1H, d, J = 7.8Hz), 8.05 (1H, s), 9.45 (1H, brs),10.28 (1H, s), 10.75 (1H, s). FAB-MS: 539 (M + H)⁺ 178

NMR: δ 1.33-1.46 (1H, m), 1.42 (3H, d, J = 6.9Hz), 1.60- 1.90 (5H, m),2.88-3.00 (2H, m), 3.15-3.25 (2H, m), 3.32- 3.53 (4H, m), 4.62 (1H, q, J= 6.8Hz), 6.95 (1H, d, J = 8.3Hz), 7.23 (1H, dd, J = 8.8, 2.5Hz),7.41-7.46 (1H, m), 7.48- 7.56 (3H, m), 7.62-7.77 (5H, m), 9.66 (1H,brs), 10.45 (1H, s), 10.74 (1H, s). FAB-MS: 470 (M + H)⁺ 179

NMR: δ 1.18-1.37 (1H, m), 1.50-1.68 (3H, m), 1.72-1.92 (2H, m), 2.18(3H, s), 2.53-2.70 (2H, m), 3.14-3.26 (2H, m), 3.37 (2H, s), 4.31-4.44(2H, m), 7.26-7.60 (8H, m), 8.00 (1H, d, J = 7.9Hz), 8.68 (1H, s), 10.22(1H, brs), 10.40 (1H, s), 10.44-10.54 (1H, m). FAB-MS: 440 (M + H)⁺ 180

NMR: δ 1.20-1.37 (1H, m), 1.45 (3H, d, J = 6.3Hz), 1.54- 1.68 (3H, m),1.70-1.88 (2H, m), 2.58-2.74 (2H, m), 3.14- 3.26 (2H, m), 4.26-4.40 (2H,m), 4.63 (1H, q, J = 6.7Hz), 6.96 (1H, d, J = 8.8Hz), 7.32-7.40 (2H, m),7.46-7.60 (4H, m), 7.67 (1H, s), 8.03 (1H, d, J = 7.8Hz), 8.64 (1H, s),9.99 (1H, brs), 10.50-10.58 (1H, m), 10.75 (1H, s). FAB-MS: 490 (M + H)⁺181

NMR: δ 1.22 (3H, t, J = 7.3Hz), 1.50-1.70 (2H, m), 1.81 (1H, d, J =11.8Hz), 2.36 (1H, d, J = 12.2Hz), 2.50-2.70 (5H, m), 2.85 (2H, t, J =6.8Hz), 2.88-3.12 (3H, m), 3.25 (3H, s), 3.29-3.40 (2H, m), 4.37 (1H,dd, J = 14.1, 5.4Hz), 4.57 (1H, dd, J = 14.1Hz, 5.4Hz), 7.20 (1H, d, J =8.3Hz), 7.45-7.60 (6H, m), 7.64 (1H, dd, J = 8.3, 1.5), 7.79 (1H, d, J =1.4Hz), 8.07 (1H, dd, J = 8.3, 1.5Hz), 8.67 (1H, s), 9.88 (brs), 10.65() 1H, s). FAB-MS 514 (M + H)⁺

TABLE 35 Ex Structure (salt) DATA 182

NMR: δ 0.84 (3H, t, J = 7.1Hz), 1.08-1.38 (8H, m), 1.42 (3H, d, J =6.8Hz), 1.45-1.57 (1H, m), 2.46-2.54 (2H, m), 2.65- 2.78 (1H, m),2.79-2.97 (1H, m), 4.20-4.37 (1H, m), 4.47-4.57 (1H, m), 4.63 (1H, q, J= 6.9Hz), 6.96 (1H, d, J = 8.8Hz), 7.34 (1H, dd, J = 8.8, 2.5Hz), 7.41(2H, d, J = 6.4Hz), 7.46-7.57 (4H, m), 7.65 (1H, d, J = 1.9Hz), 8.04(1H, d, J = 7.8Hz), 8.53 (1H, s), 10.06 (1H, brs), 10.45 (1H, s), 10.75(1H, s). FAB-MS: 486 (M + H)⁺ 183

NMR: δ 1.35-1.55 (4H, m), 1.65-1.78 (5H, m), 1.82-1.92 (1H, m),1.93-2.02 (1H, br), 2.07-2.17 (1H, m), 2.52- 2.65 (3H, m), 2.80-2.87(2H, m), 2.92-3.22 (6H, m), 3.26 (3H, s), 3.48-3.58 (2H, m), 7.17-7.22(1H, m), 7.36-7.45 (4H, m), 7.45-7.54 (3H, m), 7.62 (1H, s), 7.92-7.98(1H, m), 8.10 (1H, s), 10.41 (1H, s). FAB-MS: 537 (M + H)⁺ 184

NMR: δ 0.95 (3H, t, J = 7.1Hz), 1.05 (3H, t, J = 7.1Hz), 1.28- 1.68 (4H,m), 1.42 (3H, d, J = 6.8Hz), 1.90-2.23 (1H, m), 2.60-2.78 (1H, m),2.80-2.91 (1H, m), 3.07-4.00 (8H, m), 4.63 (1H, q, J = 6.9Hz), 6.95 (1H,d, J = 8.3Hz), 7.26 (1H, dd, J = 8.8, 2.4Hz), 7.37-7.52 (6H, m), 7.53(1H, d, J = 2.4Hz), 7.92-8.00 (1H, m), 8.08-8.20 (1H, m), 10.27 (1H, s),10.74 (1H, s). FAB-MS: 555 (M + H)⁺ 185

NMR: δ 1.42 (3H, d, J = 6.8Hz), 2.74-2.87 (2H, m), 3.28- 3.40 (4H, m),4.17-4.28 (2H, m), 4.44-4.57 (2H, m), 4.63 (1H, q, J = 6.9Hz), 6.66-6.73(1H, m), 6.83-6.88 (1H, m), 6.96 (1H, d, J = 8.8Hz), 7.32-7.61 (8H, m),7.67 (1H, s), 8.01-8.07 (1H, m), 8.08-8.12 (1H, s), 8.64 (1H, s), 10.50(1H, s), 10.59 (1H, s), 10.75 (1H, s). FAB-MS: 534 (M + H)⁺ 186

NMR: δ 0.88-1.94 (16H, m), 2.52-2.88 (4H, m), 3.12-3.70 (5H, m), 4.50(2H, d, J = 4.4Hz), 7.21 (1H, d, J = 8.3Hz), 7.42-7.66 (7H, m), 7.81(1H, s), 8.03 (1H, d, J = 7.8Hz), 8.54 (1H, s), 9.19 (1H, brs), 10.82(1H, s). FAB-MS: 510 (M + H)⁺ 187

NMR: δ 0.85 (12H, t, J = 6.8Hz), 1.89-2.00 (2H, m), 2.53- 2.58 (2H, m),2.67-2.72 (4H, m), 2.82-2.87 (2H, m), 3.26 (3H, s), 4.53 (2H, d, J =4.9Hz), 7.21 (1H, d, J = 8.3Hz), 7.42-7.63 (7H, m), 7.54 (1H, d, J =1.9Hz), 7.88-7.94 (1H, m), 8.70 (1H, d, J = 1.4Hz), 9.31 (1H, brs),10.64 (1H, s). FAB-MS: 498 (M + H)⁺ 188

NMR: δ 1.76-1.88 (1H, m), 1.95-2.13 (2H, m), 2.17-2.32 (1H, m),2.71-2.90 (2H, m), 3.16-3.28 (1H, m), 3.30-3.42 (1H, m), 4.29-4.56 (3H,m), 5.95 (2H, d, J = 7.3Hz), 6.36 (1H, dd, J = 8.8, 2.4Hz), 6.64 (1H,dd, J = 6.3, 2.0Hz), 6.79 (1H, dd, J = 8.3, 4.9Hz), 7.38-7.45 (2H, m),7.47-7.58 (4H, m), 8.02-8.08 (1H, m), 8.09-8.18 (2H, m), 8.78- 8.92 (2H,m), 9.42 (1H, s), 10.75 (1H, brs), 10.92 (1H, d, J = 2.9Hz). FAB-MS: 564(M + H)⁺

TABLE 36 Ex Structure (salt) DATA 189

NMR: δ 0.85 (3H, d, J = 6.6Hz), 1.22 (3H, d, J = 6.6Hz), 2.03 (3H, s),3.08-3.20 (1H, m), 3.27-3.40 (2H, m) 4.32-4.47 (2H, m), 4.48-4.60 (2H,m), 7.43-7.59 (6H, m), 8.04-8.12 (2H, m), 8.16 (1H, d, J = 8.3Hz),8.77-8.83 (2H, m), 9.41 (1H, s), 10.20 (1H, s), 10.91 (1H, s). FAB-MS:488 (M + H)⁺ 190

NMR: δ 0.97 (3H, t, J = 7.1Hz), 2.66-3.14 (2H, m), 4.48 (2H, s), 4.62(2H, s), 7.37-7.43 (2H, m), 7.46-7.58 (4H, m), 8.04 (1H, dd, J = 7.8,1.5Hz), 8.09-8.20 (2H, m), 8.38 (2H, s), 8.76-8.85 (2H, m), 8.97 (2H, d,J = 5.9Hz), 9.43 (1H, s), 10.87 (1H, s), 11.47 (1H, brs). FAB-MS: 479(M + H)⁺ 191

NMR: δ 0.88-1.03 (2H, m), 1.04-1.22 (2H, m), 1.23-1.36 (2H, m),1.44-1.48 (2H, m), 1.62-1.71 (1H, m), 1.78-1.95 (2H, m), 2.01-2.10 (1H,m), 2.35 (3H, s), 2.66-2.98 (5H, m), 4.34-4.42 (1H, m), 4.49-4.57 (1H,m), 7.38 (2H, d, J = 8.3Hz), 7.42-7.47 (2H, m), 7.47-7.58 (4H, m),7.60-7.68 (3H, m), 8.04-8.17 (3H, m), 8.75 (1H, s), 8.81 (1H, s), 9.41(1H, s), 10.09 (1H, brs), 10.96 (1H, s). FAB-MS: 653 (M + H)⁺ 192

NMR: δ 0.82-0.92 (6H, m), 2.50 (2H, t, J = 5.2Hz), 2.82-2.92 (1H, m),3.40 (2H, t, J = 5.2Hz), 3.61 (0.2H, s), 3.66 (1.8H, s), 4.08-4.16 (1H,m), 7.25-7.35 (3H, m), 7.36-7.48 (3H, m), 7.82-7.88 (1H, m), 7.89-7.96(2H, m), 8.20-8.25 (1H, m), 8.47 (1H, s), 8.68 (1H, brs), 9.00 (1H, s).FAB-MS: 446 (M + H)⁺ 193

NMR: δ 0.99 (9H, s), 1.42 (3H, d, J = 6.9Hz), 2.51-2.69 (2H, m), 3.00(2H, s), 3.03 (3H, s), 6.94 (1H, d, J = 8.8Hz), 7.26 (1H, dd, J = 8.3,2.4Hz), 7.29-7.39 (3H, m), 7.40-7.53 (3H, m), 7.57 (1H, d, J = 2.4Hz),7.90 (1H, brs), 8.28 (1H, s), 10.24 (1H, s), 10.72. FAB-MS: 502 (M +H)⁺. 194

NMR: δ 1.12-1.15 (3H, m), 1.22 (6H, d, J = 5.8Hz), 1.42 (3H, d, J =6.9Hz), 2.85-3.30 (4H, m), 3.40-4.00 (4H, m), 4.63 (1H, q, J = 6.6Hz),6.95 (1H, d, J = 8.8Hz), 7.30 (1H, d, J = 8.8Hz), 7.40-7.54 (6H, m),7.60 (1H, s), 7.96 (1H, d, J = 8.3Hz), 8.26 (1H, brs), 10.31 (1H, s),10.75 (1H, s). FAB-MS: 513 (M + H)⁺. 195

NMR: δ 0.67-0.85 (6H, m), 1.30-1.55 (3. 5H, m), 1.57-2.08 (6.5H, m),2.60-2.77 (2H, m), 2.82-3.14 (3H, m), 3.33- 3.65 (5H, m), 4.42-4.53(0.5H, m), 4.58-4.68 (1.5H, m), 6.95 (1H, d, J = 8.3Hz), 7.25-7.65(7.3H, m), 7.65-7.75 (0.7H, m), 7.87-8.20 (1.3H, m), 8.75 (0.7H, s),10.00 (0.3H, br s), 10.26-10.50 (1.2H, m), 10.75 (1H, s), 10.93 (0.5H,s). FAB-MS: 555 (M + H)⁺. 196

NMR: δ 0.77 (6H, d, J = 6.3Hz), 1.42 (3H, d, J = 6.9Hz), 1.43- 1.51 (2H,m), 1.60-1.70 (1H, m), 2.00-2.17 (2H, m), 2.31- 2.50 (2H, m), 3.36 (2H,t, J = 6.3Hz), 3.00-4.10 (3H, m), 4.63 (1H, q, J = 6.8Hz), 6.93 (1H, d,J = 8.8Hz), 7.24 (1H, dd, J = 8.8, 2.4Hz), 7.32-7.50 (6H, m), 7.58 (1H,d, J = 2.5Hz), 7.90 (1H, d, J = 8.3Hz), 8.19 (1H, s), 10.26 (1H, s),10.71 (1H, s). FAB-MS: 502 (M + H)⁺.

TABLE 37

Ex A— DATA 197

H: 2.63 FP: 582 198

H: 1.93 FP: 458 199

H: 2.28 FP: 529 200

H: 2.18 FP: 460 201

H: 2.28 FP: 496 202

H: 2.02 FP: 505 203

H: 2.26 FP: 525 204

H: 2.16 FP: 528 205

H: 1.92 FP: 481 206

H: 1.94 FP: 460 207

H: 2.15 FP: 474 208

H: 2.07 FP: 474 209

H: 2.90 FP: 480 210

H: 2.06 FP: 587 211

H: 2.60 FP: 562 212

H: 2.52 FP: 553 213

H: 2.60 FP: 548 214

H: 2.58 FP: 575 215

H: 2.86 FP: 534 216

H: 2.15 FP: 505 217

H: 2.15 FP: 514 218

H: 2.61 FP: 641 219

H: 2.32 FP: 547 220

H: 2.14 FP: 482

TABLE 38 221

H: 2.26 FP: 498 222

H: 3.23 FP: 482 223

H: 2.26 FP: 460 224

H: 2.39 FP: 524 225

H: 2.44 FP: 493 226

H: 2.38 FP: 504 227

H: 2.25 FP: 554 228

H: 2.27 FP: 536 229

H: 2.97 FP: 502 230

H: 2.72 FP: 570 231

H: 2.88 FP: 578 232

H: 2.55 FP: 566

TABLE 39 No Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

TABLE 40 No Structure 23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

1. A benzamide compound or salt thereof, represented by formula (I):

wherein

L: a lower alkylene; D ring: a 3,4-dihydro-2H-1,4-benzoxazine ring; Ering: a monocyclic or bicyclic hydrocarbon ring, or a 5- to 12-memberedmonocyclic or bicyclic heteroaromatic ring containing 1 to 4 atomsselected from the group consisting of N, S, and O; G ring: a 4- to12-membered monocyclic or bicyclic heterocycle containing 1 to 4 atomsselected from the group consisting of N, S, and O; R¹ to R⁹: the same ordifferent, a hydrogen atom, a halogen atom, a lower alkyl, ahalogen-substituted lower alkyl, —OH, —SH, —O-lower alkyl, —O-loweralkyl-NH-lower alkyl, —O-lower alkyl-N(lower alkyl)₂, ═O, —NH₂,—NH-lower alkyl, —N(lower alkyl)₂, —S-lower alkyl, —SO-lower alkyl,—SO₂-lower alkyl, —CN, —COOH, —C(═O)—O-lower alkyl, —C(═O)—NH₂,—C(═O)—NH-lower alkyl, —C(═O)—N(lower alkyl)₂, —NH—C(═O)—O-lower alkyl,—NH—SO₂-lower alkyl, —SO₂—NH₂, —SO₂—NH-lower alkyl, —C(═O)-lower alkyl,—NO₂ or a 5- to 8-membered saturated or partially unsaturated monocyclicheterocycle which contains one N atom and may further contain oneheteroatom selected from the group consisting of N, S, and O; R¹⁰: ahydrogen atom or a lower alkyl; R¹¹ to R¹⁵: the same or different, ahydrogen atom, a halogen atom, a lower alkyl, a halogen-substitutedlower alkyl, —OH, —O-lower alkyl, —S-lower alkyl, —SO-lower alkyl,—SO₂-lower alkyl, ═O, —C(═O)H, —C(═O)-lower alkyl, —COOH, —CN, —NH₂,—NH-lower alkyl, —N(lower alkyl)₂, —C(═O)—NH₂, —C(═O)—NH-lower alkyl,—C(═O)—N(lower alkyl)₂, —C(═O)-aryl, —C(═O)—NH-aryl, —NH—C(═O)-loweralkyl, —NH—C(═O)-aryl, —NH—SO₂-lower alkyl, —N(lower alkyl)-SO₂-loweralkyl, -lower alkylene-NH—SO₂-lower alkyl, -lower alkylene-NH—SO₂-aryl,—C(═O)—O-lower alkyl, -lower alkylene-OH, -lower alkylene-C(═O)—NH-loweralkyl, -lower alkylene-C(═O)—N (lower alkyl)₂, -loweralkylene-C(═O)—NH₂, -lower alkylene-C(═O)—OH, -lower alkylene-O-loweralkyl, -lower alkylene-S-lower alkyl, -lower alkylene-O—C(═O)-loweralkyl, -lower alkylene-NH-lower alkyl, -lower alkylene-N(lower alkyl)₂,-lower alkylene-aryl, a cycloalkyl, an aryl -(4- to 12-memberedmonocyclic or bicyclic heterocycle containing 1 to 4 atoms selected fromthe group consisting of N, S, and O), —O-(4- to 12-membered monocyclicor bicyclic heterocycle containing 1 to 4 atoms selected from the groupconsisting of N, S, and O), -lower alkylene-(4- to 12-memberedmonocyclic or bicyclic heterocycle containing 1 to 4 atoms selected fromthe group consisting of N, S, and O), —C(═O)-(4- to 12-memberedmonocyclic or bicyclic heterocycle containing 1 to 4 atoms selected fromthe group consisting of N, S, and O), -lower alkylene-N(lower alkyl)-(4-to 12-membered monocyclic or bicyclic heterocycle containing 1 to 4atoms selected from the group consisting of N, S, and O), or—C(═O)—NH-(4- to 12-membered monocyclic or bicyclic heterocyclecontaining 1 to 4 atoms selected from the group consisting of N, S, andO); and the above monocyclic or bicyclic heterocycle may be substitutedby halogen atom(s), lower alkyl(s), —O-lower alkyl, or —OH.
 2. Thecompound according to claim 1 or salt thereof, wherein the E ring is abenzene ring or a thiophene ring.
 3. The compound according to claim 2or salt thereof, wherein the A group is:

and wherein the G ring and R¹³ to R¹⁵ have the same meanings as informula (I).
 4. The compound according to claim 3 or salt thereof,wherein the G ring is a 5- to 8-membered saturated or partiallyunsaturated monocyclic heterocycle which contains one N atom and mayfurther contain one heteroatom selected from the group consisting of N,S, and O and the ring nitrogen atom is bonded to L.
 5. The compoundaccording to claim 3 or salt thereof, wherein the G ring is a ringselected from the group consisting of morpholine, piperidine, orpyrrolidine and the ring nitrogen atom of the ring group is bonded to L.6. The compound according to claim 3 or a salt thereof, wherein the Ering is benzene.
 7. The compound according to claim 3 or a salt thereof,wherein the D ring, together with the groups represented by R⁶ to R⁹ tobe bonded thereto, form a group represented by formula (II):

wherein R^(6a): a hydrogen atom, a lower alkyl, or a halogen-substitutedlower alkyl, and R^(7a) and R^(8b): the same or different, a hydrogenatom, a halogen atom, a lower alkyl, or a halogen-substituted loweralkyl.
 8. The compound according to claim 2 or salt thereof, wherein thegroup represented by A is:

and wherein R^(11a) and R^(12a): the same or different, a hydrogen atom,a lower alkyl, a halogen-substituted lower alkyl, —O-lower alkyl,—SO₂-lower alkyl, —C(═O)H, —C(═O)-lower alkyl, —CN, —NH₂, —NH-loweralkyl, —N(lower alkyl)₂, —C(═O)—NH₂, —C(═O)—NH-lower alkyl,—C(═O)—N(lower alkyl)₂, —C(═O)-aryl, —C(═O)—NH-aryl, —NH—C(═O)-loweralkyl, —NH—C(═O)-aryl, —NH—SO₂-lower alkyl, —N(lower alkyl)—SO₂-loweralkyl, -lower alkylene-NH—SO₂-lower alkyl, -lower alkylene-NH—SO₂-aryl,—C(═O)—O-lower alkyl, -lower alkylene-OH, -lower alkylene-C(═O)—NH-loweralkyl, -lower alkylene-C(═O)—N(lower alkyl)₂, -lower alkylene-C(═O)—NH₂,-lower alkylene-C(═O)—OH, -lower alkylene-O-lower alkyl, -loweralkylene-S-lower alkyl, -lower alkylene-O—C(═O)-lower alkyl, -loweralkylene-NH-lower alkyl, -lower alkylene-N(lower alkyl)₂, -loweralkylene-aryl, a cycloalkyl, an aryl, -(4- to 12-membered monocyclic orbicyclic heterocycle containing 1 to 4 atoms selected from the groupconsisting of N, S, and O), —O-(4- to 12-membered monocyclic or bicyclicheterocycle containing 1 to 4 atoms selected from the group consistingof N, S, and O), -lower alkylene-(4- to 12-membered monocyclic orbicyclic heterocycle containing 1 to 4 atoms selected from the groupconsisting of N, S, and O), —C(═O)-(4- to 12-membered monocyclic orbicyclic heterocycle containing 1 to 4 atoms selected from the groupconsisting of N, S, and O), -lower alkylene-N(lower alkyl)-(4- to12-membered monocyclic or bicyclic heterocycle containing 1 to 4 atomsselected from the group consisting of N, S, and O), or —C(═O)—NH-(4- to12-membered monocyclic or bicyclic heterocycle containing 1 to 4 atomsselected from the group consisting of N, S, and O), and the abovemonocyclic or bicyclic heterocycle may be substituted by a halogen atom,a lower alkyl, —O-lower alkyl, or —OH.
 9. The compound according toclaim 8 or salt thereof, wherein the D ring, together with the groupsrepresented by R⁶ to R⁹ to be bonded thereto, form a group representedby formula (II):

wherein R^(6a) and R^(6b): the same or different, a hydrogen atom, alower alkyl, or a halogen-substituted lower alkyl, and R^(7a), R^(8a),R^(7b), and R^(8b): the same or different, a hydrogen atom, a halogenatom, a lower alkyl, or a halogen-substituted lower alkyl.
 10. Thecompound according to claim 8 or a salt thereof, wherein R^(11a) is alower alkyl and R^(12a) is a group selected from the group consisting of-lower alkylene-O-lower alkyl, -lower alkylene-S-lower alkyl, -loweralkylene-NH-lower alkyl, -lower alkylene-N(lower alkyl)₂, -loweralkylene-OH, -lower alkylene-C(═O)—NH-lower alkyl, -loweralkylene-C(═O)—N(lower alkyl)₂, -lower alkylene-aryl, a cycloalkyl, anaryl, -(monocyclic or bicyclic heterocycle), and -loweralkylene-(monocyclic or bicyclic heterocycle).
 11. The compoundaccording to claim 1 or a salt thereof, wherein the D ring is3,4-dihydro-2H-1,4-benzoxazine and at least two of R⁶ to R⁹ areindependently ═O and a lower alkyl.
 12. The compound according to claim1 or a salt thereof, which isN-(2,4-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-2-(piperidin-1-ylmethyl)biphenyl-4-carboxamide.13. The compound according to claim 1 or a salt thereof, which is2-(piperidin-1-ylmethyl)-N-(2,2,4-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)biphenyl-4-carboxamide.14. The compound according to claim 1 or a salt thereof, which isN-[(2R)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]-2-(piperidin-1-ylmethyl)biphenyl-4-carboxamide.15. The compound according to claim 1 or a salt thereof, which is2-{[ethyl(2-hydroxy-2-methylpropyl)amino]methyl}-N-(2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)biphenyl-4-carboxamide.16. The compound according to claim 1 or a salt thereof, which is atleast one compound selected from the group consisting of2-[(4-methyl-1,3′-bipiperidin-1′-yl)methyl]-N-(2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)biphenyl-4-carboxamide,and2-{[isobutyl(2-piperidin-1-ylethyl)amino]methyl}-N-(2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)biphenyl-4-carboxamide.17. A pharmaceutical composition comprising the benzamide compoundaccording to claim 1, or a salt thereof, and a pharmaceuticallyacceptable carrier.
 18. A method for treating pain, which comprisesadministering a therapeutically effective amount of the benzamidecompound according to claim 1 or a salt thereof, to a subject in needthereof.
 19. The compound according to claim 1 or a salt thereof,wherein said 5- to 8-membered saturated or partially unsaturatedmonocyclic heterocycle which contains one N atom and may further containone heteroatom selected from the group consisting of N, S, and O is apyrrolidine ring, a piperidine ring, a piperazine ring, an azepane ring,a diazepane ring, a morpholine ring, a thiomorpholine ring, or atetrahydropyridine ring.